U.S. patent application number 12/990909 was filed with the patent office on 2011-05-19 for 6-pyridin-3-yl-3,4-dihydro-1h-quinolin-2-one derivatives and related compounds as inhibitors of the human aldosterone synthase cyp11b2.
This patent application is currently assigned to Universitat des Saarlandes. Invention is credited to Rolf W. Hartmann, Ralf Heim, Simon Lucas.
Application Number | 20110118241 12/990909 |
Document ID | / |
Family ID | 41152526 |
Filed Date | 2011-05-19 |
United States Patent
Application |
20110118241 |
Kind Code |
A1 |
Hartmann; Rolf W. ; et
al. |
May 19, 2011 |
6-Pyridin-3-YL-3,4-Dihydro-1H-Quinolin-2-One Derivatives and
Related Compounds as Inhibitors of the Human Aldosterone Synthase
CYP11B2
Abstract
The invention provides compounds of the general formula (I)
which are inhibitors of the human aldosterone synthase, and also
pharmaceutical compositions containing these compounds, and the use
of these compounds and other heteroaryl substituted quinolinone
derivatives for the treatment of hyperaldosteronism and/or
disorders or diseases that are mediated by 11 .beta.-hydroxylase
(CYP11 B1). ##STR00001##
Inventors: |
Hartmann; Rolf W.;
(Saarbrucken, DE) ; Heim; Ralf; (Saarbrucken,
DE) ; Lucas; Simon; (Homburg, DE) |
Assignee: |
Universitat des Saarlandes
Saarbrucken
DE
|
Family ID: |
41152526 |
Appl. No.: |
12/990909 |
Filed: |
May 5, 2009 |
PCT Filed: |
May 5, 2009 |
PCT NO: |
PCT/EP2009/003217 |
371 Date: |
January 28, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61051437 |
May 8, 2008 |
|
|
|
Current U.S.
Class: |
514/224.2 ;
514/230.5; 514/249; 514/256; 514/294; 514/307; 514/312; 514/338;
514/339; 544/105; 544/333; 544/354; 544/52; 544/92; 546/144;
546/158; 546/271.7; 546/277.7; 546/94 |
Current CPC
Class: |
A61P 5/40 20180101; A61P
9/10 20180101; C07D 215/227 20130101; A61P 13/12 20180101; C07D
471/04 20130101; A61P 7/10 20180101; A61P 3/04 20180101; A61P 9/04
20180101; C07D 401/14 20130101; A61P 7/00 20180101; A61P 5/42
20180101; C07D 221/06 20130101; A61P 29/00 20180101; A61P 9/12
20180101; A61P 9/00 20180101; C07D 401/04 20130101 |
Class at
Publication: |
514/224.2 ;
546/158; 546/277.7; 546/144; 546/94; 544/52; 544/333; 544/105;
546/271.7; 544/354; 544/92; 514/312; 514/339; 514/307; 514/294;
514/256; 514/230.5; 514/338; 514/249 |
International
Class: |
A61K 31/5415 20060101
A61K031/5415; C07D 401/10 20060101 C07D401/10; C07D 471/06 20060101
C07D471/06; C07D 417/10 20060101 C07D417/10; C07D 413/10 20060101
C07D413/10; A61K 31/4709 20060101 A61K031/4709; A61K 31/4439
20060101 A61K031/4439; A61K 31/4725 20060101 A61K031/4725; A61K
31/4745 20060101 A61K031/4745; A61K 31/506 20060101 A61K031/506;
A61K 31/538 20060101 A61K031/538; A61K 31/498 20060101 A61K031/498;
A61K 31/536 20060101 A61K031/536; A61P 9/12 20060101 A61P009/12;
A61P 5/40 20060101 A61P005/40; A61P 9/04 20060101 A61P009/04; A61P
13/12 20060101 A61P013/12; A61P 9/10 20060101 A61P009/10; A61P 9/00
20060101 A61P009/00; A61P 3/04 20060101 A61P003/04; A61P 29/00
20060101 A61P029/00 |
Foreign Application Data
Date |
Code |
Application Number |
May 6, 2008 |
DE |
10 2008 022 221.6 |
Claims
1. A compound of the general formula (I) ##STR00179## in which Z
stands for C.dbd.O, C.dbd.S, or SO.sub.2; U stands independently
for CR.sup.5R.sup.6, NR.sup.7, O, S, SO, or SO.sub.2; X stands
independently for CR.sup.5R.sup.6, NR.sup.7, O, or S; Y stands
independently for CR.sup.5R.sup.6, NR.sup.7, O, or S; A stands for
CR.sup.8R.sup.9, C.dbd.O, C.dbd.S, NR.sup.10, O, S, or SO.sub.2; b
is 0 or 1; n is 0 or 1; m is 0 or 1; provided that not more than
one of U, X, and Y stands for NR.sup.7, O, or S; and X and Y do not
stand for O or S, and X or Y only stands for NR.sup.7 in a position
vicinal to U, when U stands for SO or SO.sub.2, wherein, when at
least one of n or m is not equal to zero, the bond between U and X
or U and Y, respectively, or X and Y can be a C.dbd.C or C.dbd.N
double bond; Het is a ring system containing 1 or 2 rings, and at
least one of the rings is aromatic and contains 5 or 6 ring atoms,
of which at least one is nitrogen, and the other ring can be
saturated or unsaturated and comprises from 5 to 7 ring atoms;
while the ring system can contain additional 1 to 5 heteroatoms
selected from the group consisting of N, S, and O, provided that
not more than two heteroatoms are selected from the group
consisting of S and O; and the ring system can be substituted by
from one to four substituents R.sup.11, with the following
provisos: when R.sup.1 and R.sup.2 do not together form part of a
ring system, 1) 3-pyridyl has at position 6 no substituents other
than H, when Het stands for 3-pyridyl; and 2) Het is not a
substituted or unsubstituted pyridyl or pyrimidyl when Z stands for
C.dbd.O, n is 0, m is 1, and X stands for CR.sup.5R.sup.6, U stands
for CR.sup.5R.sup.6, and R.sup.2 is not NO.sub.2; R.sup.1 is
selected from the group consisting of H; C.sub.1-4 alkyl, C.sub.2-4
alkenyl, C.sub.3-7 cycloalkyl, C.sub.1-4 alkylcarbonyl, and
C.sub.1-4 alkoxycarbonyl, each of which can be substituted by from
one to three substituents R.sup.a, wherein R.sup.a is independently
selected from the group consisting of optionally partially or
completely halogenated C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4
alkylthio, and C.sub.1-4 alkylcarbonyl and also hydroxyl, nitro,
and cyano, or can be partially or completely halogenated with
independent halogen atoms; aryl C.sub.1-4 alkyl and heterocyclyl
C.sub.1-4 alkyl, which can in each case be substituted on the ring
or at least on one ring by from one to four substituents R.sup.b,
wherein R.sup.b is selected from the group consisting of C.sub.1-4
alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkylthio, C.sub.1-4
alkylcarbonyl, C.sub.1-4 alkylsulfonyl, whose alkyl moieties may be
partially or completely halogenated with independent halogen atoms,
halogen, hydroxyl, nitro, cyano, --NR.sup.c.sub.2,
--CONR.sup.c.sub.2, and SO.sub.2NR.sup.c.sub.2, wherein R.sup.c is
independently selected from the group consisting of H and C.sub.1-4
alkyl; R.sup.2 is selected from the group consisting of H;
C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.3-7
cycloalkyl, C.sub.5-7 cycloalkenyl, C.sub.1-4 alkoxy, C.sub.1-4
alkylcarbonyl, C.sub.1-4 alkoxycarbonyl, alkylsulfonyl, which in
each case can be substituted by from one to three substituents
R.sup.a, wherein R.sup.a has the meanings stated above, or can be
partially or completely halogenated with independent halogen atoms;
aryl C.sub.1-4 alkyl, aryl C.sub.0-4 alkylsulfonyl, heterocyclyl
C.sub.1-4 alkyl, which can in each case be substituted on the ring
or at least on one ring by from one to four substituents R.sup.b,
wherein R.sup.b has the meanings stated above; halogen, hydroxyl,
nitro, cyano, --NR.sup.c.sub.2, --CONR.sup.c.sub.2, and
--SO.sub.2NR.sup.c.sub.2, wherein R.sup.c has the meanings stated
above; or R.sup.1 and R.sup.2 form, together with the atoms to
which they are bonded, an unsaturated nitrogen-containing five
membered to seven membered ring comprising 1 or 2 unsaturated bonds
and may, in addition to the nitrogen atom to which the R.sup.1
group is bonded, also contain a hetero atom or a
heteroatom-containing group selected from the group consisting of
O, S and NR.sup.7, and can be substituted by from one to four
substituents R.sup.12; R.sup.3 and R.sup.4 independently have the
meanings stated for R.sup.2; R.sup.5 and R.sup.6 are independently
selected from the group consisting of H; C.sub.1-4 alkyl, C.sub.3-7
cycloalkyl, hydroxyl C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4
alkoxycarbonyl, C.sub.1-4 alkylthio, whose alkyl moieties can be
partially or completely halogenated with independent halogen atoms;
halogen, hydroxyl, nitro, cyano, --NR.sup.c.sub.2, and
NR.sup.cCOR.sup.d, wherein R.sup.c has the meanings stated above
and R.sup.d is selected from the group consisting of C.sub.1-4
alkyl, C.sub.3-7 cycloalkyl, C.sub.1-4 alkoxy, whose alkyl moieties
can be partially or completely halogenated with independent halogen
atoms, and wherein R.sup.5 or R.sup.6 may be bonded to a carbon
atom forming part of a double bond, R.sup.7 is selected from the
group consisting of H; C.sub.1-4 alkyl, and C.sub.3-7 cycloalkyl,
which in each case can be substituted by from one to three
substituents R.sup.a, wherein R.sup.a has the meanings stated
above, or can be partially or completely halogenated with
independent halogen atoms; and aryl C.sub.1-4 alkyl, which can be
substituted on the ring or at least on one ring by from one to four
substituents R.sup.b, wherein R.sup.b has the meanings stated
above; R.sup.8 and R.sup.9 are independently selected from the
group consisting of H; C.sub.1-4 alkyl, C.sub.3-7 cycloalkyl,
C.sub.1-4 alkoxy, C.sub.1-4 alkylthio, C.sub.1-4 alkylcarbonyl,
C.sub.1-4 alkoxycarbonyl, which can in each case be substituted by
from one to three substituents R.sup.a, wherein R.sup.a has the
meanings stated above, or can be partially or completely
halogenated with independent halogen atoms; halogen, hydroxyl;
aryl, aryl C.sub.1-4 alkyl, heterocyclyl, heterocyclyl C.sub.1-4
alkyl, which can be substituted on the ring or at least on one ring
by from one to four substituents R.sup.b, wherein R.sup.b has the
meanings stated above; or R.sup.8 and R.sup.9 form, together with
the carbon atom to which they are bonded, a cyclopropane ring;
R.sup.10 is selected from the group consisting of H; C.sub.1-4
alkyl, C.sub.3-7 cycloalkyl, which in each case can be substituted
by from one to three substituents R.sup.a, wherein R.sup.a has the
meanings stated above, or can be partially or completely
halogenated with independent halogen atoms; aryl, aryl C.sub.1-4
alkyl, heterocyclyl, and heterocyclyl C.sub.1-4 alkyl, each of
which can be substituted on the or at least one ring by from one to
four substituents R.sup.b, wherein R.sup.b has the meanings stated
above; R.sup.11 is independently selected from the group consisting
of C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.3-7
cycloalkyl, C.sub.5-7 cycloalkenyl, C.sub.1-4 alkoxy, C.sub.1-4
alkylthio, C.sub.1-4 alkylcarbonyl, C.sub.1-4 alkoxycarbonyl,
C.sub.1-4 alkylsulfonyl, which can in each case be substituted by
from one to three substituents R.sup.a, wherein R.sup.a has the
meanings stated above, or can be partially or completely
halogenated with independent halogen atoms; aryl, heterocyclyl,
aryl C.sub.0-4 alkylsulfonyl, aryl C.sub.1-4 alkyl, and
heterocyclyl C.sub.1-4 alkyl, which can in each case be substituted
on the ring or at least on one ring by from one to four
substituents R.sup.b, wherein R.sup.b has the meanings stated
above, halogen, hydroxyl, nitro, cyano, --NR.sup.c.sub.2,
--CONR.sup.c.sub.2, and --SO.sub.2NR.sup.c.sub.2, wherein R.sup.c
has the meanings stated above; and R.sup.12 is independently
selected from the group consisting of C.sub.1-4 alkyl, C.sub.2-4
alkenyl, C.sub.2-4 alkynyl, C.sub.3-7 cycloalkyl, C.sub.5-7
cycloalkenyl, which can in each case be substituted by from one to
three substituents R.sup.a, wherein R.sup.a has the meanings stated
above, or can be partially or completely halogenated with
independent halogen atoms; aryl, heterocyclyl, aryl C.sub.1-4
alkyl, and heterocyclyl C.sub.1-4 alkyl, which can in each case be
substituted on the ring or at least on one ring by from one to four
substituents R.sup.b, wherein R.sup.b has the meanings stated
above, and is also selected from the group consisting of optionally
partially or completely halogenated C.sub.1-4 alkoxy, hydroxyl,
halogen, nitro, cyano, and NR.sup.c.sub.2 when R.sup.12 is bonded
to a carbon atom, wherein R.sup.c has the meanings stated above; or
a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1, wherein the bond between U and
X and U and Y, respectively, or X and Y, is a single bond, or a
pharmaceutically acceptable salt thereof.
3. A compound according to claim 1, wherein Z stands for C.dbd.O,
or a pharmaceutically acceptable salt thereof.
4. A compound according to claim 1, wherein R.sup.1 stands for H or
C.sub.1-4 alkyl, or a pharmaceutically acceptable salt thereof.
5. A compound according to claim 1, wherein R.sup.1 and R.sup.2
together with the atoms, to which they are bound, form an
unsaturated nitrogen-containing five to seven membered ring having
1 or 2 unsaturated bond(s) and, in addition to the nitrogen atom,
to which R.sup.1 is bound, may contain a heteroatom or a
heteroatom-containing group selected from the group consisting of
O, S and NR.sup.7 and may be substituted with one to four
substituents R.sup.12, wherein R.sup.12 is as defined in claim 1,
or a pharmaceutically acceptable salt thereof.
6. A compound according to claim 1, wherein the unsaturated
nitrogen containing ring is an unsubstituted five or six membered
ring having one or two unsaturated bond(s) and no further
heteroatom, or a pharmaceutically acceptable salt thereof.
7. A compound according to claim 1, wherein U stands for S or
CR.sup.5R.sup.6, wherein R.sup.5 and R.sup.6 are independently
selected from H and C.sub.1-4 alkyl, X stands for CH.sub.2, and
n=0, or a pharmaceutically acceptable salt thereof.
8. A compound according to claim 1, wherein A stands for C.dbd.O or
CR.sup.8R.sup.9, wherein R.sup.8 and R.sup.9 independently stand
for H or C.sub.1-4 alkyl or A is absent (i.e. b=0), or a
pharmaceutically acceptable salt thereof.
9. A compound according to claim 1, wherein Het stands for pyridyl,
isoquinolinyl, pyrimidyl or imidazolyl, optionally substituted with
a substituent R.sup.11, wherein R.sup.11 is defined as in claim 1,
or a pharmaceutically acceptable salt thereof.
10. A compound according to claim 1 selected from
5-Pyridin-3-yl-1,3-dihydroindol-2-one
6-Isoquinolin-4-yl-3,4-dihydro-1H-quinolin-2-one
6-Isoquinolin-4-yl-1-methyl-3,4-dihydro-1H-quinolin-2-one
6-Pyridin-3-yl-3,4-dihydro-1H-quinoline-2-thione
8-Pyridin-3-yl-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-4-one
8-Nitro-6-pyridin-3-yl-3,4-dihydro-1H-quinolin-2-one
7-Pyridin-3-yl-4H-benzo[1,4]thiazin-3-one
8-Chloro-6-pyridin-3-yl-3,4-dihydro-1H-quinolin-2-thione
9-Pyridin-3-yl-1,2,6,7-tetrahydro-5H-pyrido[3,2,1-ij]quinolin-3-one
8-(5-Methoxypyridin-3-yl)-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-4-o-
ne
8-Isoquinolin-4-yl-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-4-one
9-(5-Methoxypyridin-3-yl)-1,2,6,7-tetrahydro-5H-pyrido[3,2,1-ij]quinolin--
3-one
9-Isoquinolin-4-yl-1,2,6,7-tetrahydro-5H-pyrido[3,2,1-ij]quinolin-3--
one
8-Pyridin-3-yl-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinoline-4-thione
6,6-Dimethyl-8-pyridin-3-yl-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-4-
-one
8-(5-Ethoxypyridin-3-yl)-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin--
4-one
8-(5-Trifluoromethylpyridin-3-yl)-1,2,5,6-tetrahydropyrrolo[3,2,1-ij-
]quinolin-4-one
8-(5-Fluoropyridin-3-yl)-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-4-on-
e
8-Imidazol-1-yl-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-4-one.
8-Pyridin-4-yl-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-4-one
8-Pyrimidin-5-yl-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-4-one
8-(Pyridin-4-carbonyl)-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-4-one
8-(Pyridin-3-carbonyl)-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-4-one
8-(5-Phenylpyridin-3-yl)-1,2,5,6-tetrahydropyrrolo[3,2,1]quinolin-4-one
8-(5-Isopropoxypyridin-3-yl)-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin--
4-one
8-(1-Imidazol-1-yl-ethyl)-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinoli-
n-4-one
8-[5-(4-Fluorophenyl)pyridin-3-yl]-1,2,5,6-tetrahydropyrrolo[3,2,1-
-ij]quinolin-4-one
8-[5-(3-Fluorophenyl)pyridin-3-yl]-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]qui-
nolin-4-one
8-[5-(4-Methoxyphenyl)pyridin-3-yl]-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]qu-
inolin-4-one
8-[5-(3-Methoxyphenyl)pyridin-3-yl]-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]qu-
inolin-4-one
8-[5-(2-Fluorophenyl)pyridin-3-yl]-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]qui-
nolin-4-one
8-[5-(3-Trifluoromethylphenyl)pyridin-3-yl]-1,2,5,6-tetrahydropyrrolo[3,2-
,1-ij]quinolin-4-one
8-[5-(3,4-Difluorophenyl)pyridin-3-yl]-1,2,5,6-tetrahydropyrrolo[3,2,1-ij-
]quinolin-4-one
8-[5-(3-Trifluoromethoxyphenyl)pyridin-3-yl]-1,2,5,6-tetrahydropyrrolo[3,-
2,1-ij]quinolin-4-one
8-[5-(2-Methoxyphenyl)pyridin-3-yl]-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]qu-
inolin-4-one or a pharmaceutically acceptable salt thereof.
11. (canceled)
12. Pharmaceutical composition, containing a compound of claim 1 or
a pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable carrier or excipient.
13. (canceled)
14. (canceled)
15. (canceled)
16. A composition comprising a compound according to claim 1 and at
least one other active ingredient selected from active ingredients
to counteract obesity, loop diuretics, angiotensine converting
enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs),
.quadrature.-receptor blockers, renin inhibitors, calcium channel
blockers, and 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA)
reductase inhibitors.
17. A method of treating hyperaldosteronism in a mammal wherein a
pharmaceutically effective amount of a compound according to claim
1 is administered to a patient in need thereof.
18. The method according to claim 17, wherein the treating of
hyperaldosteronism includes the treating of hypokalaemia,
hypertension, congestive heart failure, ventricular fibrillation,
renal failure, including chronic renal failure, restenosis,
atherosclerosis, syndrome X, obesity, nephropathy, postmyocardial
infarction syndrome, coronary cardiac diseases, inflammation,
increased collagen formation, vasculitis, fibrosis, including
cardiac or myocardial fibrosis, remodeling following hypertension,
endothelial dysfunction and/or edema.
19. (canceled)
Description
[0001] The invention relates to heteroaryl substituted derivatives
of quinolinones and related compounds that inhibit the human
aldosterone synthase CYP11B2, to pharmaceutical compositions
containing these derivatives, and to the use of these derivatives
and other heteroaryl substituted quinolinone derivatives for the
treatment of hyperaldosteronism and/or disorders or diseases
mediated by 11.beta.-hydroxylase (CYP11B1).
[0002] The adrenal glands of humans are divided into two regions,
the adrenal medulla and the adrenal cortex. The latter secretes a
number of hormones which are known as corticoids and fall under two
categories. Glucocorticoids (chiefly hydrocortisone and cortisol)
primarily act on hydrocarbon and glucose metabolism, and they can
secondarily retard the healing of wounds by interference with the
inflammatory process and the formation of fibrous tissue. The
second category, the mineralocorticoids, primarily participates in
the retention of sodium and the excretion of potassium. The most
important and most effective mineralocorticoid is aldosterone.
[0003] The aldosterone secretion is regulated by a large number of
signals: the plasma concentrations of sodium and potassium and the
renin-angiotensin-aldosterone system (RAAS) extending over a number
of stages. In this system, renin is secreted by the kidneys in
response to low blood pressure and the renin liberates angiotensin
I from a precursor peptide. Angiotensin I is in turn dissociated to
angiotensin II, which comprises 8 amino acids and is a potent
vasoconstrictor. In addition, it acts as a hormone for stimulation
of the release of aldosterone (Weber, K. T. & Brilla, C. G.,
Circulation 83, 1849-1865 (1991).
[0004] The key enzyme of the mineralocorticoid biosynthesis,
CYP11B2 (aldosterone synthase), a mitochondrial cytochrome P450
enzyme, catalyzes the formation of the most potent
mineralocorticoid aldosterone from its steroidal substrate
11-deoxycorticosterone (Kawamoto, T. et al., Proc. Natl. Acad. Sci.
US A 89:1458-1462 (1992). Hyperaldosteronism (excessive plasma
aldosterone concentrations) can participate in the cause and
progression of clinical pictures such as congestive heart failure,
myocardial fibrosis, ventricular arrhythmia, and the stimulation of
cardiac fibroblasts, cardiac hypertrophy, renal underperfusion and
hypertension (Brilla, C. G., Herz 25, 299-306 (2000). In
particular, in the case of patients having chronic heart failure or
renal underperfusion or renal artery stenoses, the physiological
action of the renin angiotensin system (RAAS) is replaced by
pathophysiological activation thereof (Young, M., Funder, J. W.,
Trends Endocrinol. Metab. 11, 224-226 (2000). Angiotensin II
mediated vasoconstriction and the water and sodium restriction
caused by the increased aldosterone level creates an additional
stress on the already insufficient myocardium. In the sense of a
"Circulus vitiosus" there results further reduction in renal
perfusion and an increased renin secretion. Additionally, both the
increased plasma aldosterone and angiotensin II levels and locally
secreted aldosterone in the heart induce fibrotic structural
changes in the myocardium, resulting in the formation of a
myocardial fibrosis leading to further reduction of the cardiac
performance (Brilla, C. G., Cardiovasc. Res. 47, 1-3 (2000);
Lijnen, P. & Petrov, V. J. Mol. Cell. Cardiol. 32, 865-879
(2000).
[0005] Fibrotic structural changes are characterized by the
formation of tissue distinguished by an abnormally high amount of
fibrotic material (primarily collagen strings). Such fibroses are
helpful in some situations, such as the healing of wounds, but can
be damaging, for example, when they interfere with the function of
internal organs. In the case of myocardial fibrosis, fibrotic
strings are present in the cardiac muscle and cause the muscle to
become stiff and inflexible with consequent impairment of the
function thereof.
[0006] Since the mortality rate of patients suffering from only
slight cardiac insufficiency is from 10% to 20%, it is highly
necessary to combat this by means of a suitable pharmacotherapy.
Despite long-term therapy using digitalis glycosides, diuretics,
ACE inhibitors, or AT II antagonists, the plasma aldosterone levels
of the patients remain high, and the medication has no effect on
the fibrotic structural changes.
[0007] Mineralocorticoid antagonists, particularly aldosterone
blocking agents, already form the subject matter of numerous
patents. Thus the steroidal mineralocorticoid antagonist
spironolactone
(17-hydroxyl-7-.alpha.-mercapto-3-oxo-17-.alpha.-pregn-4-ene-21-carboxyli-
c acid .gamma.-lactone acetate) (Aldactone.RTM.) blocks aldosterone
receptors competitively with aldosterone and thus impedes the
receptor mediated aldosterone action. US 2002/0013303, U.S. Pat.
No. 6,150,347, and U.S. Pat. No. 6,608,047 describe the
administration of spironolactone for the treatment or prophylaxis
of cardiovascular disorders and myocardial fibrosis whilst
maintaining the normal electrolyte and water balance of the
patients.
[0008] The "Randomized Aldactone Evaluation Study" (RALES) (Pitt,
B. et al., New Engl. J. Med. 341, 709-717 (1999) has impressively
shown that the administration of the aldosterone receptor
antagonist spironolactone (Aldactone.RTM.), when used as a
supplement to the basic treatment with ACE inhibitors and loop
diuretics, was capable of causing a significant improvement in the
survival rate of severely cardially insufficient patients, since it
inhibited the action of aldosterone to an adequate extent
(Kulbertus, H., Rev. Med. Liege 54, 770-772 (1999). However, the
application of spironolactone was accompanied by serious side
effects such as gynaecomastia, dysmenorrhoea, and pectoral pain,
caused by the steroidal structure of the substance and the
resultant reciprocal actions thereof with other steroid receptors
(Pitt, B. et al., New Eng. J. Med. 341, 709-717 (1999); MacFadyen,
R. J. et al., Cardiovasc. Res. 35, 30-34 (1997); Soberman, J. E.
& Weber, K. T., Curr. Hypertens. Rep. 2, 451-456 (2000).
[0009] Mespirenone (15,16-methylene-17-spirolactone) and its
derivatives have been regarded as a promising alternative to
spironolactone since they show only a low percentage of the
anti-androgen action of spironolactone (Losert, W. et al., Drug
Res. 36, 1583-1600 (1986); Nickisch, K. et al., J. Med. Chem.
30(8), 1403-1409 (1987); Nickisch, K. et al., J. Med. Chem. 34,
2464-2468 (1991); Agarwal, M. K., Lazar, G., Renal Physiol.
Biochem. 14, 217-223 (1991). Mespirenone blocks the aldosterone
biosynthesis as part of an overall mineralocorticoid biosynthesis
inhibition (Weindel, K. et al., Arzneimittelforschung 41(9),
946-949 (1991). However mespirenone, like spironolactone, inhibits
the aldosterone biosynthesis only at very high concentrations.
[0010] WO 01/34132 describes methods for the treatment, prophylaxis
or blocking of pathogenic changes resulting from vascular lesions
(restenoses) in mammals by administration of an aldosterone
antagonist, namely eplerenone (an aldosterone receptor antagonist)
or related structures, which are partially epoxysteroidal and can
all be derived from 20-spiroxanes.
[0011] WO 96/40255, US 2002/0123485, US 2003/0220312, and US
2003/0220310 describe therapeutic methods for the treatment of
cardiovascular disorders, myocardial fibrosis or cardiac
hypertrophy by the use of a combination therapy with an
angiotensine II antagonist and an epoxysteroidal aldosterone
receptor antagonist such as eplerenone or epoxymexrenone.
[0012] The recently published study EPHESUS ("Eplerenone's Heart
Failure Efficacy and Survival Study", 2003) was able to
substantiate the results of RALES. Supplementarily to the basic
therapy applied, the first selective steroidal mineralocorticoid
receptor antagonist eplerenone (Inspras.RTM.) distinctly reduces
morbidity and mortality in the case of patients having acute
myocardial infarction and also reduces the occurrence of
complications, eg, decrease of the left ventricular ejection
fraction and cardiac failure (Pitt, B. et al., N. Eng. J. Med. 348,
1390-1382 (2003).
[0013] RALES and EPHESUS have clearly shown that aldosterone
antagonists provide a therapy option which should not be
underestimated. However, their side effect profile demands a search
for substances which differ from spironolactone in structure and
action mechanism. A very promising alternative is given in this
case by non-steroid inhibitors of the mineralocorticoid
biosynthesis, for it is better to reduce the pathologically
increased aldosterone concentration than merely to block the
mineralocorticoid receptors. CYP11B2, as key enzyme, could in this
context be a starting point for achieving specific inhibitors. An
excessive generalized liberation of aldosterone and, in particular,
the cardiac production of aldosterone could be reduced by specific
inhibition of the biosynthesis, which might in turn reduce
pathological structural changes in the myocardium.
[0014] Selective aldosterone synthase inhibitors might be a
promising class of substances which, following a myocardial
infarction, might promote healing of the impaired myocardium tissue
with reduced cicatrization and thus diminish the occurrence of
serious complications.
[0015] The human steroid-11.beta.-hydroxylase CYP11B1, the key
enzyme for biosynthesis of glucocorticoids in humans, shows a
homology of more than 93% with human CYP11B2 (Kawamoto, T. et al.,
Proc. Natl. Acad. Sci. USA 89, 1458-1462 (1992); Taymans, S. E. et
al., J. Clin. Endocrinol. Metab. 83, 1033-1036 (1998). Despite the
high structural and functional similarities of these two enzymes it
would be desirable if strong inhibiting substances of the
aldosterone synthase did not influence
steroid-11.beta.-hydroxylase. Moreover, preferably non-steroid
inhibitors of the aldosterone synthase should be used as
therapeutic agents, since fewer side effects on the endocrine
system are to be expected than with steroid inhibitors. The
development of selective CYP11B2 inhibitors that do not influence
the CYP11B1 is hampered by the high homology of CYP11B1 with
CYP11B2.
[0016] Also, the inhibitors should not interfere with other P450
(CYP) enzymes to any great extent.
SUMMARY OF THE INVENTION
[0017] It has been found that certain heteroaryl substituted
derivatives of quinolinones and related compounds are suitable for
selective inhibition of the aldosterone synthase CYP11B2.
[0018] The invention thus relates to a compound of the general
formula (I)
##STR00002##
in which [0019] Z stands for C.dbd.O, C.dbd.S, or SO.sub.2; [0020]
U stands independently for CR.sup.5R.sup.6, NR.sup.7, O, S, SO, or
SO.sub.2; [0021] X stands independently for CR.sup.5R.sup.6,
NR.sup.7, O, or S; [0022] Y stands independently for
CR.sup.5R.sup.6, NR.sup.7, O, or S; [0023] A stands for
CR.sup.8R.sup.9, C.dbd.O, C.dbd.S, NR.sup.10, O, S, or SO.sub.2;
[0024] b is 0 or 1; [0025] n is 0 or 1; [0026] m is 0 or 1; [0027]
provided that not more than one of U, X, and Y stands for NR.sup.7,
O, or S; and X and Y do not stand for O or S, and X or Y only
stands for NR.sup.7 in a position vicinal to U, [0028] when U
stands for SO or SO.sub.2, [0029] wherein, when at least one of n
or m is not equal to zero, the bond between U and X or [0030] U and
Y, respectively, or X and Y can be a C.dbd.C or C.dbd.N double
bond; [0031] Het is a ring system containing 1 or 2 rings, and at
least one of the rings is aromatic and contains 5 or 6 ring atoms,
of which at least one is nitrogen, and the other ring can be
saturated or unsaturated and comprises from 5 to 7 ring atoms;
while the ring system can contain additional 1 to 5 heteroatoms
selected from the group consisting of N, S, and O, provided that
not more than two heteroatoms are selected from the group
consisting of S and O; and the ring system can be substituted by
from one to four substituents R.sup.11, with the following
provisos: [0032] when R.sup.1 and R.sup.2 do not together form part
of a ring system, [0033] 1) 3-pyridyl has at position 6 no
substituents other than H, when Het stands for 3-pyridyl; and
[0034] 2) Het is not a substituted or unsubstituted pyridyl or
pyrimidyl when Z stands for C.dbd.O, n is 0, m is 1, and X stands
for CR.sup.5R.sup.6, U stands for CR.sup.5R.sup.6, and R.sup.2 is
not NO.sub.2; [0035] R.sup.1 is selected from the group consisting
of H; C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.3-7 cycloalkyl,
C.sub.1-4 alkylcarbonyl, and C.sub.1-4 alkoxycarbonyl, each of
which can be substituted by from one to three substituents R.sup.a,
wherein R.sup.a is independently selected from the group consisting
of optionally partially or completely halogenated C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, C.sub.1-4 alkylthio, and C.sub.1-4 alkylcarbonyl
and also hydroxyl, nitro, and cyano, or can be partially or
completely halogenated with independent halogen atoms; aryl
C.sub.1-4 alkyl and heterocyclyl C.sub.1-4 alkyl, which can in each
case be substituted on the ring or at least on one ring by from one
to four substituents R.sup.b, wherein R.sup.b is selected from the
group consisting of C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4
alkylthio, C.sub.1-4 alkylcarbonyl, C.sub.1-4 alkylsulfonyl, whose
alkyl moieties may be partially or completely halogenated with
independent halogen atoms, halogen, hydroxyl, nitro, cyano,
--NR.sup.c.sub.2, --CONR.sup.c.sub.2, and SO.sub.2NR.sup.c.sub.2,
wherein R.sup.c is independently selected from the group consisting
of H and C.sub.1-4 alkyl; [0036] R.sup.2 is selected from the group
consisting of H; C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4
alkynyl, C.sub.3-7 cycloalkyl, C.sub.5-7, cycloalkenyl, C.sub.1-4
alkoxy, C.sub.1-4 alkylcarbonyl, C.sub.1-4 alkoxycarbonyl,
C.sub.1-4 alkylsulfonyl, which in each case can be substituted by
from one to three substituents R.sup.a, wherein R.sup.a has the
meanings stated above, or can be partially or completely
halogenated with independent halogen atoms; aryl C.sub.1-4 alkyl,
aryl C.sub.0-4 alkylsulfonyl, heterocyclyl C.sub.1-4 alkyl, which
can in each case be substituted on the ring or at least on one ring
by from one to four substituents R.sup.b, wherein R.sup.b has the
meanings stated above; halogen, hydroxyl, nitro, cyano,
--NR.sup.c.sub.2, --CONR.sup.c.sub.2, and --SO.sub.2NR.sup.c.sub.2,
wherein R.sup.c has the meanings stated above; [0037] or [0038]
R.sup.1 and R.sup.2 form, together with the atoms to which they are
bonded, an unsaturated nitrogen-containing five membered to seven
membered ring comprising 1 or 2 unsaturated bonds and may, in
addition to the nitrogen atom to which the R.sup.1 group is bonded,
also contain a hetero atom or a heteroatom-containing group
selected from the group consisting of O, S and NR.sup.7, and can be
substituted by from one to four substituents R.sup.12; [0039]
R.sup.3 and R.sup.4 independently have the meanings stated for
R.sup.2; [0040] R.sup.5 and R.sup.6 are independently selected from
the group consisting of H; C.sub.1-4 alkyl, C.sub.3-7 cycloalkyl,
hydroxyl C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4
alkoxycarbonyl, C.sub.1-4 alkylthio, whose alkyl moieties can be
partially or completely halogenated with independent halogen atoms;
halogen, hydroxyl, nitro, cyano, --NR.sup.c.sub.2, and
NR.sup.cCOR.sup.d, wherein R.sup.c has the meanings stated above
and R.sup.d is selected from the group consisting of C.sub.1-4
alkyl, C.sub.3-7 cycloalkyl, C.sub.1-4 alkoxy, whose alkyl moieties
can be partially or completely halogenated with independent halogen
atoms, and wherein R.sup.5 or R.sup.6 may be bonded to a carbon
atom forming part of a double bond, [0041] R.sup.7 is selected from
the group consisting of H; C.sub.1-4 alkyl, and C.sub.3-7
cycloalkyl, which in each case can be substituted by from one to
three substituents R.sup.a, wherein R.sup.a has the meanings stated
above, or can be partially or completely halogenated with
independent halogen atoms; and aryl C.sub.1-4 alkyl, which can be
substituted on the ring or at least on one ring by from one to four
substituents R.sup.b, wherein R.sup.b has the meanings stated
above; [0042] R.sup.8 and R.sup.9 are independently selected from
the group consisting of H; C.sub.1-4 alkyl, C.sub.3-7 cycloalkyl,
C.sub.1-4 alkoxy, C.sub.1-4 alkylthio, C.sub.1-4 alkylcarbonyl,
C.sub.1-4 alkoxycarbonyl, which can in each case be substituted by
from one to three substituents R.sup.a, wherein R.sup.a has the
meanings stated above, or can be partially or completely
halogenated with independent halogen atoms; halogen, hydroxyl;
aryl, aryl C.sub.1-4 alkyl, heterocyclyl, heterocyclyl C.sub.1-4
alkyl, which can be substituted on the ring or at least on one ring
by from one to four substituents R.sup.b, wherein R.sup.b has the
meanings stated above; [0043] or [0044] R.sup.8 and R.sup.9 form,
together with the carbon atom to which they are bonded, a
cyclopropane ring; [0045] R.sup.10 is selected from the group
consisting of H; C.sub.1-4 alkyl, C.sub.3-7 cycloalkyl, which in
each case can be substituted by from one to three substituents
R.sup.a, wherein R.sup.a has the meanings stated above, or can be
partially or completely halogenated with independent halogen atoms;
aryl, aryl C.sub.1-4 alkyl, heterocyclyl, and heterocyclyl
C.sub.1-4 alkyl, each of which can be substituted on the or at
least one ring by from one to four substituents R.sup.b, wherein
R.sup.b has the meanings stated above; [0046] R.sup.11 is
independently selected from the group consisting of C.sub.1-4
alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.3-7 cycloalkyl,
C.sub.5-7 cycloalkenyl, C.sub.1-4 alkoxy, C.sub.1-4 alkylthio,
C.sub.1-4 alkylcarbonyl, C.sub.1-4 alkoxycarbonyl, C.sub.1-4
alkylsulfonyl, which can in each case be substituted by from one to
three substituents R.sup.a, wherein R.sup.a has the meanings stated
above, or can be partially or completely halogenated with
independent halogen atoms; aryl, heterocyclyl, aryl C.sub.0-4
alkylsulfonyl, aryl C.sub.1-4 alkyl, and heterocyclyl C.sub.1-4
alkyl, which can in each case be substituted on the ring or at
least on one ring by from one to four substituents R.sup.b, wherein
R.sup.b has the meanings stated above, halogen, hydroxyl, nitro,
cyano, --NR.sup.c.sub.2, --CONR.sup.c.sub.2, and
--SO.sub.2NR.sup.c.sub.2, wherein R.sup.c has the meanings stated
above; and [0047] R.sup.12 is independently selected from the group
consisting of C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4
alkynyl, C.sub.3-7 cycloalkyl, C.sub.5-7 cycloalkenyl, which can in
each case be substituted by from one to three substituents R.sup.a,
wherein R.sup.a has the meanings stated above, or can be partially
or completely halogenated with independent halogen atoms; aryl,
heterocyclyl, aryl C.sub.1-4 alkyl, and heterocyclyl C.sub.1-4
alkyl, which can in each case be substituted on the ring or at
least on one ring by from one to four substituents R.sup.b, wherein
R.sup.b has the meanings stated above, and is also selected from
the group consisting of optionally partially or completely
halogenated C.sub.1-4 alkoxy, hydroxyl, halogen, nitro, cyano, and
NR.sup.c.sub.2 when R.sup.12 is bonded to a carbon atom, wherein
R.sup.c has the meanings stated above; or a pharmaceutically
acceptable salt thereof.
[0048] The invention further relates to said compounds of formula
(I) and the pharmaceutically acceptable salts thereof as a
medicinal substance and pharmaceutical composition containing said
compounds or pharmaceutically acceptable salts thereof and a
pharmaceutically acceptable vehicle or adjuvant.
[0049] Furthermore, the invention relates to the use of the
compounds of formula (I) or a pharmaceutical composition containing
the same for the treatment of hyperaldosteronism.
[0050] Furthermore, the invention relates to the use of compounds
of the general formula (II)
##STR00003##
in which [0051] Z stands for C.dbd.O, C.dbd.S, or SO.sub.2; [0052]
U stands independently for CR.sup.5R.sup.6, NR.sup.7, O, S, SO, or
SO.sub.2; [0053] X stands independently for CR.sup.5R.sup.6,
NR.sup.7, O, or S; [0054] Y stands independently for
CR.sup.5R.sup.6, NR.sup.7, O, or S; [0055] A stands for
CR.sup.8R.sup.9, C.dbd.O, C.dbd.S, NR.sup.10, O, S, or SO.sub.2;
[0056] b is 0 or 1; [0057] n is 0 or 1; [0058] m is 0 or 1; [0059]
provided that not more than one of U, X, and Y stands for NR.sup.7,
O, or S; and X and Y do not stand for O or S, and X or Y only
stands for NR.sup.7 in a position vicinal to U, when U stands for
SO or SO.sub.2, [0060] wherein, when at least one of n or m is not
equal to zero, the bond between U and X or U and Y, respectively,
or X and Y can be a C.dbd.C or C.dbd.N double bond; [0061] Het is a
saturated or unsaturated ring system containing 1 or 2 rings, and
at least one of the rings is aromatic and contains 5 or 6 ring
atoms, of which at least one is nitrogen, and the other ring can be
saturated or unsaturated and comprises from 5 to 7 ring atoms;
wherein the ring system can contain additional 1 to 5 heteroatoms
selected from the group consisting of N, S, and O, provided that
not more than two heteroatoms are selected from the group
consisting of S and O; and the ring system can be substituted by
from one to four substituents R.sup.11; [0062] R.sup.1 is selected
from the group consisting of H; C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
C.sub.3-7 cycloalkyl, C.sub.1-4 alkylcarbonyl, and C.sub.1-4
alkoxycarbonyl, each of which can be substituted by from one to
three substituents R.sup.a, wherein R.sup.a is independently
selected from the group consisting of optionally partially or
completely halogenated C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4
alkylthio, C.sub.1-4 alkylcarbonyl and hydroxyl, nitro, and cyano,
or can be partially or completely halogenated with independent
halogen atoms; aryl C.sub.1-4 alkyl and heterocyclyl C.sub.1-4
alkyl, which can in each case be substituted on the ring or at
least on one ring by from one to four substituents R.sup.b, R.sup.b
being selected from the group consisting of C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, C.sub.1-4 alkylthio, C.sub.1-4 alkylcarbonyl,
C.sub.1-4 alkylsulfonyl, whose alkyl moieties may be partially or
completely halogenated with independent halogen atoms, halogen,
hydroxyl, nitro, cyano, --NR.sup.c.sub.2, --CONR.sup.c.sub.2, and
SO.sub.2NR.sup.c.sub.2, wherein R.sup.c is independently selected
from the group consisting of H and C.sub.1-4 alkyl; [0063] R.sup.2
is selected from the group consisting of H; C.sub.1-4 alkyl,
C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.3-7 cycloalkyl,
C.sub.5-7 cycloalkenyl, C.sub.1-4 alkoxy, C.sub.1-4 alkylcarbonyl,
C.sub.1-4 alkoxycarbonyl, C.sub.1-4 alkylsulfonyl, which can in
each case be substituted by from one to three substituents R.sup.a,
wherein R.sup.a has the meanings stated above, or can be partially
or completely halogenated with independent halogen atoms; aryl
C.sub.1-4 alkyl, aryl C.sub.0-4 alkylsulfonyl, heterocyclyl
C.sub.1-4 alkyl, which can in each case be substituted on the ring
or at least on one ring with from one to four substituents R.sup.b,
wherein R.sup.b has the meanings stated above; halogen, hydroxyl,
nitro, cyano, --NR.sup.c.sub.2, --CONR.sup.c.sub.2, and
--SO.sub.2NR.sup.c.sub.2, wherein R.sup.c has the meanings stated
above; [0064] or [0065] R.sup.1 and R.sup.2 form, together with the
atoms to which they are bonded, an unsaturated nitrogen-containing
five membered to seven membered ring which contains 1 or 2
unsaturated bonds and, in addition to the nitrogen atom to which
the R.sup.1 group is bonded, can also contain a hetero atom or a
heteroatom-containing group selected from the group consisting of
O, S, and NR.sup.7 and can be substituted by from one to four
substituents R.sup.12; [0066] R.sup.3 and R.sup.4 independently
have the meanings stated for R.sup.2; [0067] R.sup.5 and R.sup.6
are independently selected from the group consisting of H;
C.sub.1-4 alkyl, C.sub.3-7 cycloalkyl, hydroxyl C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl, C.sub.1-4 alkylthio,
whose alkyl moieties can be partially or completely halogenated
with independent halogen atoms; halogen, hydroxyl, nitro, cyano,
--NR.sup.c.sub.2, and NR.sup.cCOR.sup.d, wherein R.sup.c has the
meanings stated above and R.sup.d is selected from the group
consisting of C.sub.1-4 alkyl, C.sub.3-7 cycloalkyl, C.sub.1-4
alkoxy, whose alkyl moieties can be partially or completely
halogenated with independent halogen atoms, and R.sup.5 or R.sup.6
may be bonded to a carbon atom forming part of a double bond,
[0068] R.sup.7 is selected from the group consisting of H;
C.sub.1-4 alkyl, C.sub.3-7 cycloalkyl, which in each case can be
substituted by from one to three substituents R.sup.a, wherein
R.sup.a has the meanings stated above, or can be partially or
completely halogenated with independent halogen atoms; and aryl
C.sub.1-4 alkyl, which can be substituted on the ring or at least
on one ring by from one to four substituents R.sup.b, wherein
R.sup.b has the meanings stated above; [0069] R.sup.8 and R.sup.9
are independently selected from the group consisting of H;
C.sub.1-4 alkyl, C.sub.3-7 cycloalkyl, C.sub.1-4 alkoxy, C.sub.1-4
alkylthio, C.sub.1-4 alkylcarbonyl, and C.sub.1-4 alkoxycarbonyl,
which can in each case be substituted by from one to three
substituents R.sup.a, wherein R.sup.a has the meanings stated
above, or can be partially or completely halogenated with
independent halogen atoms; halogen, hydroxyl; aryl, aryl C.sub.1-4
alkyl, heterocyclyl, heterocyclyl C.sub.1-4 alkyl, which can be
substituted on the ring or at least on one ring by from one to four
substituents R.sup.b, wherein R.sup.b has the meanings stated
above; [0070] or [0071] R.sup.8 and R.sup.9 form, together with the
carbon atom to which they are bonded, a cyclopropane ring; [0072]
R.sup.10 is selected from the group consisting of H; C.sub.1-4
alkyl, C.sub.3-7 cycloalkyl, which in each case can be substituted
by from one to three substituents R.sup.a, wherein R.sup.a has the
meanings stated above, or can be partially or completely
halogenated with independent halogen atoms; aryl, aryl C.sub.1-4
alkyl, heterocyclyl, and heterocyclyl C.sub.1-4 alkyl, each of
which can be substituted on the ring by from one to four
substituents R.sup.b, wherein R.sup.b has the meanings stated
above; [0073] R.sup.11 is independently selected from the group
consisting of C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4
alkynyl, cycloalkyl, C.sub.5-7 cycloalkenyl, C.sub.1-4 alkoxy,
C.sub.1-4 alkylthio, C.sub.1-4 alkylcarbonyl, C.sub.1-4
alkoxycarbonyl, C.sub.1-4 alkylsulfonyl, which can in each case be
substituted by from one to three substituents R.sup.a, wherein
R.sup.a has the meanings stated above, or can be partially or
completely halogenated with independent halogen atoms; aryl,
heterocyclyl, aryl C.sub.0-4 alkylsulfonyl, aryl C.sub.1-4 alkyl,
and heterocyclyl C.sub.1-4 alkyl, which can in each case be
substituted on the ring or at least on one ring by from one to four
substituents R.sup.b, wherein R.sup.b has the meanings stated
above, halogen, hydroxyl, nitro, cyano, --NR.sup.c.sub.2,
--CONR.sup.c.sub.2, and --SO.sub.2NR.sup.c.sub.2, wherein R.sup.c
has the meanings stated above; and [0074] R.sup.12 is independently
selected from the group consisting of C.sub.1-4 alkyl, C.sub.2-4
alkenyl, C.sub.2-4 alkynyl, C.sub.3-7 cycloalkyl, C.sub.5-7
cycloalkenyl, which can in each case be substituted by from one to
three substituents R.sup.a, wherein R.sup.a has the meanings stated
above, or can be partially or completely halogenated with
independent halogen atoms; aryl, heterocyclyl, aryl C.sub.1-4
alkyl, and heterocyclyl C.sub.1-4 alkyl, which can in each case be
substituted on the ring or at least on one ring by from one to four
substituents R.sup.b, wherein R.sup.b has the meanings stated
above, and, when R.sup.12 is bonded to a carbon atom, is further
selected from the group consisting of optionally partially or
completely halogenated C.sub.1-4 alkoxy, hydroxyl, halogen, nitro,
cyano, and NR.sup.c.sub.2, wherein R.sup.c has the meanings stated
above; or a pharmaceutically acceptable salt thereof for the
treatment of hyperaldosteronism.
[0075] There follow definitions of the chemical expressions used in
the formulas and formula schemes. In general, the expressions used
have the meanings normally accorded thereto by the person skilled
in the art.
[0076] "C.sub.1-4 alkyl" stands for methyl, ethyl, n-propyl,
isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl.
[0077] "C.sub.2-4 alkenyl" stands for an alkenyl radical containing
from 2 to 4 carbon atoms, such as vnyl, prop-1-en-1-yl, allyl,
isopropenyl, but-(1, 2, or 3)-en-1-yl or 1-methyl-1-propenyl,
1-methyl-2-propenyl, or 2-methyl-2-propen-1-yl.
[0078] "C.sub.2-4 alkynyl" stands for ethynyl, prop-(1 or
2)-yn-1-yl, but-(1, 2, or 3)-yn-1-yl and
1-methyl-2-propyn-1-yl.
[0079] "C.sub.3-7 cycloalkyl" stands for cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, and cycloheptyl.
[0080] "C.sub.5-7 cycloalkenyl" stands for the various isomers of
cyclopentenyl, cyclohexenyl, and cycloheptenyl.
[0081] "C.sub.1-4 alkoxy" stands for methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl, which is
bonded to the rest of the molecule via an oxygen atom. Examples
thereof are methoxy (methyloxy), ethoxy (ethyloxy), n-propoxy
(n-propyloxy), and n-butoxy (n-butyloxy).
[0082] "C.sub.1-4 alkylthio" stands for methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl, which is
bonded to the rest of the molecule via a sulfur atom. Examples
thereof are methylthio, ethylthio, n-propylthio, and
n-butylthio.
[0083] "C.sub.1-4 alkylcarbonyl" stands for methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl, which is
bonded to the rest of the molecule via a carbonyl group. Examples
thereof are acetyl, propionyl, 2-methylpropanoyl, butanoyl, and
pentanoyl.
[0084] "C.sub.1-4 alkoxycarbonyl" stands for a C.sub.1-4 alkoxy
radical (or alkyloxy radical) having the meanings stated above,
which is bonded to the rest of the molecule via a carbonyl group.
Examples thereof are methoxycarbonyl, ethoxycarbonyl, and
propyloxycarbonyl.
[0085] "C.sub.1-4 alkylsulfonyl" stands for methyl, ethyl,
n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl,
which is bonded to the rest of the molecule via a sulfonyl group
(--SO.sub.2--).
[0086] "Aryl", as used herein, stands for carbocyclic radicals
containing from 6 to 13 carbons and having one or two rings, at
least one ring being an aromatic six membered ring linked to the
rest of the molecule. Examples thereof are phenyl, 1 and
2-naphthyl, biphenylyl, indanyl, indenyl,
5,6,7,8-tetrahydronaphth-(1 or 2)-yl. Phenyl is preferred.
[0087] "Aryl C.sub.1-4 alkyl" stands for aryl having the meanings
stated above which is joined to a C.sub.1-4 alky group having the
meanings stated above which is in turn bonded to the rest of the
molecule. Examples thereof are benzyl, phenethyl, and
phenylpropyl.
[0088] "Aryl C.sub.0-4 alkylsulfonyl" stands for aryl having the
meanings stated above, which is either directly bonded to a
sulfonyl group (--SO.sub.2--) (C is zero, ie there is no alkyl
present), or is joined to C.sub.1-4 alkyl, which is bonded to the
rest of the molecule via a sulfonyl group.
[0089] "Heterocyclyl", as used herein, stands for saturated,
partially unsaturated, maximally unsaturated, and fully aromatic
heterocyclic ring systems having one or two rings each having from
5 to 7 ring members, which are directly linked to the rest of the
molecule via a carbon or nitrogen atom. The heterocyclic compounds
can contain N, O, and S as hetero atoms. The number of hetero atoms
varies, but there are usually not more than one or two oxygen or
sulfur atoms within, the ring system, while there can be up to 8
nitrogen atoms.
[0090] Example of saturated heterocyclyl having the meanings stated
above are pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidyl,
piperazinyl, morpholino, tetrahydrofuryl, tetrahydrothienyl,
homopiperidinyl, isoxazolidinyl, oxazolidinyl, 1,3-diazepanyl, and
1,3-thiazolidynyl.
[0091] Examples of partially unsaturated heterocyclyl having the
meanings stated above are 2,3-dihydropyridyl, 1,2-dihydrofuryl,
1,2-dihydrothienyl, 2,3-dihydrothiazolyl, 2,3-dihydropyrrol,
2,3-dihydropyridine, 2,3-dihydropyrimidine,
5,6,7,8-tetrahydroquinoline, 5,6,7,8-tetrahydro-isoquinoline,
indolinyl, chromanyl, 2,3-dihydroindolyl,
5,6,7,8-tetrahydroquinoxalinyl,
4H-2,3-dihydropyrido[3,2-b][1,4]oxazynyl, and
5,6-dihydroimidazo[1,5-a]pyridyl.
[0092] Examples of maximally unsaturated heterocyclyl having the
meanings stated above are 2H-pyrane, 4H-thiopyrane, 2H-chromene,
4H-1,3-benzothiazine, 4H-pyrido[3,2-b][1,4]oxazine, and
2H-quinolizinyl.
[0093] Examples of fully aromatic heterocyclyl are furyl, thienyl,
1,3-thiazolyl, 1H-benzimidazolyl, 1- and 2-benzofuranyl,
benzothiazolyl, benzoxazolyl, 2,3-bipyridyl, quinazolinyl,
quinolyl, quinoxalinyl, cinnolinyl, dithiazolyl, imidazolidinyl,
imidazolinyl, imidazolyl, indazolyl, indolyl, isoquinolyl,
isoindolyl, isothiazolidinyl, isothiazolyl, isoxazolyl,
naphthyridinyl, oxadiazolyl, oxazolyl, phthalazinyl, pteridinyl,
purinyl, pyridazinyl, pyrazinyl, pyrazolyl, pyrazolinyl,
pyridazinyl, pyridyl, pyrimido[4,5-c]pyridazine, pyrimidyl,
pyrrolinyl, pyrrolyl, tetrazinyl, tetrazolyl, thiadiazolyl,
thiazinyl, thiazolyl, triazinyl, and triazolyl.
[0094] The heterocyclyl groups having one ring, such as pyridyl,
piperidyl, or morpholino, are particularly preferred.
[0095] "Heterocyclyl C.sub.1-4 alkyl" is a heterocyclyl having the
meanings stated above, which is bonded to C.sub.1-4 alkyl having
the meanings stated above via a carbon or nitrogen atom, which in
turn is bonded to the rest of the molecule.
[0096] "Halogen" stands for fluorine, chlorine, bromine, and
iodine.
[0097] A partially or completely halogenated alkyl, alkenyl,
cycloalkyl, alkythio, alkyl carbonyl, alkysulfonyl, and
alkoxycarbonyl can be, for example, a CF.sub.3 group, a
CF.sub.3CF.sub.2O group, a CF.sub.3CO group, a ClCH.sub.2 group, or
a Cl.sub.3CCH.sub.2O group.
[0098] "Het" in formulas (I) and (II) is a ring system including 1
or 2 rings, and at least one of the rings is aromatic and contains
5 or 6 ring atoms, of which at least one is nitrogen, and the other
ring can be saturated or unsaturated and comprises from 5 to 7 ring
atoms; wherein the ring system can further contain from 1 to 5
heteroatoms selected from the group consisting of N, S, and O
provided that not more than two heteroatoms are selected from the
group consisting of S and O; and the ring system can be substituted
by from one to four substituents R.sup.11, wherein R.sup.11 has the
meanings stated with reference to the compounds of formula (I) or
(II).
[0099] Examples of such ring systems are 1H-benzimidazolyl,
benzothiazolyl, benzoxazolyl, 2,3-bipyridyl, quinazolinyl,
quinolyl, quinoxalinyl, quinolinyl, dithiazolyl, imidazolidinyl,
imidazolinyl, imidazolyl, indazolyl, indolyl, isoquinolyl,
isoindolyl, isothiazolidinyl, isothiazolyl, isoxazolyl,
naphthyridinyl, oxadiazolyl, oxazolyl, phthalazinyl, pteridinyl,
purinyl, pyridazinyl, pyrazinyl, pyrazolyl, pyrazolinyl,
pyridazinyl, pyridyl, pyrimido[4,5-c]pyridazine, pyrimidyl,
pyrrolinyl, pyrrolyl, tetrazinyl, tetrazolyl, thiadiazolyl,
thiazinyl, thiazolyl, triazinyl, and triazolyl.
[0100] In all embodiments of the invention, preference is given to
3-pyridyl, 4-substituted and/or 5-substituted 3-pyridyl, 4-pyridyl,
4-isoquinolyl, 1-imidazolyl, 4-imidazolyl, and 5-pyrimidyl.
[0101] The unsaturated nitrogen-containing five membered to seven
membered ring, which can be formed by R.sup.1 and R.sup.2 together
with the atoms to which they are bonded, has 1 or 2 unsaturated
bonds, namely the unsaturated bond of the benzene ring to which it
is added by condensation, and optionally another unsaturated bond
which, by reason of the bonding geometry, cannot be a triple bond.
The five membered to seven membered ring can further contain
another hetero atom or group of hetero atoms selected from the
group consisting of O, S, N, and NR.sup.7, which atoms can be
substituted by from one to three substituents R.sup.12, wherein
R.sup.12 has the meanings stated with reference to formulas (I) or
(II).
[0102] The ring is preferably a five membered or six membered ring
having one or two unsaturated bonds and not containing any further
hetero atoms.
[0103] The compounds of the formulas (I) and (H) can exhibit
chirality centers (eg, the carbons substituted by R.sup.5 and
R.sup.6 or R.sup.8 and R.sup.9 or R.sup.12). In this case, both the
mixtures of isomers and the isolated single compounds are within
the scope of the invention.
[0104] Preferred embodiments of the invention are mentioned below.
Reference to the compounds of formula (I) and/or formula (II)
should always be taken to include the pharmaceutically acceptable
salts thereof.
[0105] In a first preferred embodiment of the invention, the bond
between U and X or U and Y or X and Yin the compounds of formulas
(I) and (II) is a single bond.
[0106] In a second preferred embodiment, n is 0 or m is 0 in the
compounds of formulas (I) and (II) or in the compounds of the first
preferred embodiment.
[0107] In a third preferred embodiment, both n and m are equal to
0.
[0108] In a fourth preferred embodiment, Z denotes C.dbd.O in the
compounds of formulas (I) and (II) or in the compounds of the first
three preferred embodiments.
[0109] In a fifth preferred embodiment, Z stands for C.dbd.S or
--SO.sub.2-- in the compounds of formulas (I) and (II) or in the
compounds of the first four preferred embodiments.
[0110] In a sixth preferred embodiment, R.sup.1 stands for H or
C.sub.1-4 alkyl, C.sub.3-7 cycloalkyl, or C.sub.1-4 alkylcarbonyl
in the compounds of the formulas (I) and (II) or in the compounds
of the first five preferred embodiments, and these groups can be
partially or completely halogenated with independent halogen
atoms;
[0111] In a seventh preferred embodiment, R.sup.1 and R.sup.2 in
the compounds of formulas (I) and (II) or in the compounds of the
first six preferred embodiments form, together with the atoms to
which they are bonded, an unsaturated nitrogen-containing five
membered to seven membered ring having 1 or 2 unsaturated bonds
and, in addition to the nitrogen atom to which R.sup.1 is bonded,
can also contain a hetero atom or a group of hetero atoms selected
from the group consisting of O, S and NR.sup.7 and can be
substituted by from one to four substituents R.sup.12, wherein
R.sup.12 has the meanings stated with reference to the compounds of
formula (I) or (II).
[0112] In an eighth preferred embodiment, the unsaturated
nitrogen-containing ring in the seventh preferred embodiment is a
five membered or six membered ring having one or two unsaturated
bonds and not containing any further hetero atoms.
[0113] In a ninth preferred embodiment, the ring in the seventh or
eighth embodiment is unsubstituted or substituted by a substituent
R.sup.12, wherein R.sup.12 has the meanings stated above.
[0114] A tenth preferred embodiment of the compounds of formulas
(I) and (II) or the compounds of the first, second, and fourth to
ninth preferred embodiment are compounds in which U stands for S or
CR.sup.5R.sup.6, wherein R.sup.5 and R.sup.6 are independently
selected from the group consisting of H and C.sub.1-4 alkyl, X
stands for CH.sub.2 and n is 0.
[0115] An eleventh preferred embodiment of the compounds of
formulas (I) and (II) or the compounds of the first ten preferred
embodiments comprises compounds in which A stands for C.dbd.O or
CR.sup.8R.sup.9, wherein R.sup.8 and R.sup.9 independently stand
for the group consisting of H, C.sub.1-4 alkyl, C.sub.3-7
cycloalkyl, and aryl, which can be substituted by from 1 to 4
substituents R.sup.b, wherein R.sup.b has the meanings stated
above; or R.sup.8 and R.sup.9 form, together with the carbon atom
to which they are bonded, a cyclopropane ring, or A is
non-existent, ie b is zero.
[0116] A twelfth preferred embodiment of the compounds of formulas
(I) and (II) or the compounds of the first ten preferred
embodiments comprises compounds in which Het stands for optionally
R.sup.11-substituted 3-pyridyl, 4-pyridyl, 4-isoquinolinyl,
5-pyrimidyl, 1-imidazolyl, or 4-imidazolyl, wherein R.sup.11 has
the meanings stated above with reference to the compounds of
formula (I) or (II).
[0117] In a thirteenth preferred embodiment, R.sup.2 in the
compounds of the formulas (I) and (II) or the compounds of the
first six and the tenth to twelfth preferred embodiments, if not
joined to R.sup.1 to form a ring, stands for H; C.sub.1-4 alkyl or
C.sub.1-4 alkoxy optionally partially or completely substituted by
fluorine or chlorine; halogen; or nitro.
[0118] In a fourteenth preferred embodiment, R.sup.3 and R.sup.4 in
the compounds of the formulas (I) and (II) or the compounds of the
first thirteen preferred embodiments independently stand for H;
C.sub.1-4 alkyl or C.sub.1-4 alkoxy optionally partially or
completely substituted by fluorine or chlorine; halogen; or
nitro.
[0119] In a fifteenth preferred embodiment, one of R.sup.5 and
R.sup.6 in the compounds of formulas (I) and (II) or the compounds
of the first fourteen preferred embodiments stands for H and the
other for H; C.sub.1-4 alkyl or C.sub.1-4 alkoxy optionally
partially or completely substituted by fluorine or chlorine;
halogen; hydroxyl; or nitro.
[0120] In a sixteenth preferred embodiment, R.sup.7 in the
compounds of formulas (I) and (II) or the compounds of the first
fifteen preferred embodiments stands for H; C.sub.1-4 alkyl,
C.sub.3-7 cycloalkyl or C.sub.1-4 alkyl optionally partially or
completely substituted by fluorine.
[0121] In a seventeenth preferred embodiment, one of R.sup.8 and
R.sup.9 in the compounds of the formulas (I) and (II) or the
compounds of the first sixteen preferred embodiments stands for H
and the other stands for H, C.sub.1-4 alkyl or C.sub.1-4 alkoxy
optionally partially or completely substituted by fluorine or
chlorine; halogen or hydroxyl; or R.sup.8 and R.sup.9 form,
together with the carbon atom to which they are bonded,
cyclopropane
[0122] In an eighteenth preferred embodiment, R.sup.19 in the
compounds of formulas (I) and (II) or the compounds of the above
preferred embodiments one to ten and twelve to seventeen stands for
H; C.sub.1-4 alkyl, C.sub.3-7 cycloalkyl that may be partially or
completely substituted by fluorine; aryl, aryl C.sub.1-4 alkyl,
which can in each case be substituted on the ring or at least on
one ring by from one to four substituents R.sup.b, wherein R.sup.b
has the meanings stated above.
[0123] In a nineteenth preferred embodiment, Het in the compounds
of formulas (I) and (II) or the compounds of the above preferred
embodiments one to eighteen is either unsubstituted or is
substituted by a substituent R.sup.11, which stands for C.sub.1-4
alkyl or C.sub.1-4 alkoxy optionally partially or completely
substituted by fluorine or chlorine; halogen, hydroxyl, or phenyl,
optionally substituted by one or two substituents independently
selected from the group consisting of C.sub.1-4 alkyl, C.sub.1-4
alkoxy, C.sub.1-4 alkylthio, C.sub.1-4 alkylcarbonyl, C.sub.1-4
alkylsulfonyl, whose alkyl moieties can be partially or completely
halogenated with independent halogen atoms, halogen, hydroxyl,
nitro, cyano, --NR.sup.c.sub.2, --CONR.sup.c.sub.2, and
SO.sub.2NR.sup.c.sub.2, wherein R.sup.c is independently selected
from the group consisting of H and C.sub.1-4 alkyl.
[0124] In a twentieth preferred embodiment, the substituent
R.sup.12 in the compounds of formulas (I) and (II) or the compounds
of the above preferred embodiments seven to eighteen in which
R.sup.1 and R.sup.2 form, together with the atoms to which they are
bonded, an unsaturated nitrogen-containing ring having the meanings
stated above, stands for C.sub.1-4 alkyl optionally partially or
completely substituted by fluorine or chlorine and also for
C.sub.1-4 alkoxy optionally partially or completely substituted by
fluorine or chlorine, halogen, or hydroxyl when R.sup.12 is bonded
to a carbon atom.
[0125] Particularly preferred compounds of the invention are:
[0126] 5-Pyridin-3-yl-1,3-dihydroindol-2-one [0127]
6-Isoquinolin-4-yl-3,4-dihydro-1H-quinolin-2-one [0128]
6-Isoquinolin-4-yl-1-methyl-3,4-dihydro-1H-quinolin-2-one [0129]
6-Pyridin-3-yl-3,4-dihydro-1H-quinoline-2-thione [0130]
8-Pyridin-3-yl-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-4-one
[0131] 8-Nitro-6-pyridin-3-yl-3,4-dihydro-1H-quinolin-2-one [0132]
7-Pyridin-3-yl-4H-benzo[1,4]thiazin-3-one [0133]
8-Chloro-6-pyridin-3-yl-3,4-dihydro-1H-quinolin-2-thione [0134]
9-Pyridin-3-yl-1,2,6,7-tetrahydro-5H-pyrido[3,2,1-ij]quinolin-3-one
[0135]
8-(5-Methoxypyridin-3-yl)-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quino-
lin-4-one [0136]
8-Isoquinolin-4-yl-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-4-one
[0137]
9-(5-Methoxypyridin-3-yl)-1,2,6,7-tetrahydro-5H-pyrido[3,2,1-ij]qu-
inolin-3-one [0138]
9-Isoquinolin-4-yl-1,2,6,7-tetrahydro-5H-pyrido[3,2,1-ij]quinolin-3-one
[0139]
8-Pyridin-3-yl-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinoline-4-thio-
ne [0140]
6,6-Dimethyl-8-pyridin-3-yl-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]q-
uinolin-4-one [0141]
8-(5-Ethoxypyridin-3-yl)-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-4-on-
e [0142]
8-(5-Trifluoromethylpyridin-3-yl)-1,2,5,6-tetrahydropyrrolo[3,2,1-
-ij]quinolin-4-one [0143]
8-(5-Fluoropyridin-3-yl)-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-4-on-
e [0144]
8-Imidazol-1-yl-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-4-one-
. [0145]
8-Pyridin-4-yl-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-4-one
[0146]
8-Pyrimidin-5-yl-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-4-one
[0147]
8-(Pyridin-4-carbonyl)-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-
-4-one [0148]
8-(Pyridin-3-carbonyl)-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-4-one
[0149]
8-(5-Phenylpyridin-3-yl)-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinol-
in-4-one [0150]
8-(5-Isopropoxypyridin-3-yl)-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin--
4-one [0151]
8-(1-Imidazol-1-yl-ethyl)-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-4-o-
ne [0152]
8-[5-(4-Fluorophenyl)pyridin-3-yl]-1,2,5,6-tetrahydropyrrolo[3,2-
,1-ij]quinolin-4-one [0153]
8-[5-(3-Fluorophenyl)pyridin-3-yl]-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]qui-
nolin-4-one [0154]
8-[5-(4-Methoxyphenyl)pyridin-3-yl]-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]qu-
inolin-4-one [0155]
8-[5-(3-Methoxyphenyl)pyridin-3-yl]-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]qu-
inolin-4-one [0156]
8-[5-(2-Fluorophenyl)pyridin-3-yl]-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]qui-
nolin-4-one [0157]
8-[5-(3-Trifluoromethylphenyl)pyridin-3-yl]-1,2,5,6-tetrahydropyrrolo[3,2-
,1-ij]quinolin-4-one [0158]
8-[5-(3,4-Difluorophenyl)pyridin-3-yl]-1,2,5,6-tetrahydropyrrolo[3,2,1-ij-
]quinolin-4-one [0159]
8-[5-(3-Trifluoromethoxyphenyl)pyridin-3-yl]-1,2,5,6-tetrahydropyrrolo[3,-
2,1-ij]quinolin-4-one [0160]
8-[5-(2-Methoxyphenyl)pyridin-3-yl]-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]qu-
inolin-4-one or a pharmaceutically acceptable salt thereof.
[0161] Preferably used compounds include the following: [0162]
6-Pyridin-3-yl-3,4-dihydro-1H-quinolin-2-one [0163]
1-Methyl-6-pyridin-3-yl-3,4-dihydro-1H-quinolin-2-one [0164]
6-(5-Methoxypyridin-3-yl)-3,4-dihydro-1H-quinolin-2-one [0165]
6-(5-Methoxypyridin-3-yl)-1-methyl-3,4-dihydro-1H-quinolin-2-one
[0166] 1-Ethyl-6-pyridin-3-yl-3,4-dihydro-1H-quinolin-2-one [0167]
1-Isopropyl-6-pyridin-3-yl-3,4-dihydro-1H-quinolin-2-one [0168]
8-Chloro-6-pyridin-3-yl-3,4-dihydro-1H-quinolin-2-one [0169]
6-Pyrimidin-5-yl-3,4-dihydro-1H-quinolin-2-one and the
pharmaceutically acceptable salts thereof.
[0170] The present invention also provides prodrugs of the
compounds of the invention, which are converted in vivo to the
latter. A prodrug is an active or inactive compound which,
following administration, is modified by a physiological in vivo
action, such as hydrolysis and/or metabolism, to form a compound of
the invention, as is well known to the person skilled in the art.
Prodrugs can be divided into two classes: bioprecursor prodrugs and
carrier prodrugs, which classifications do not necessarily exclude
each other. An overview is given in The Practice of Medicinal
Chemistry, Chapters 31 and 32 (Editor: Wermuth, Academic Press, San
Diego, Calif., 2001). In general, bioprecursor prodrugs are
inactive compounds or show lower activity than the corresponding
active medicinal compound, contain one or more protective groups,
and are converted to an active form by metabolization or solvolysis
(specifically hydrolysis). Formation of the active medicinal
compound from the prodrug precursor can be based on a metabolic
process or reaction that may fall under: [0171] 1. Oxidative
reactions, such as the oxidation of alcohol and carbonyl functions
leading to acid functions, hydroxylation of aliphatic carbons,
hydroxylation of alicyclic carbon atoms, oxidation of aromatic
carbon atoms, oxidation of carbon-carbon double bonds, oxidation of
nitrogen-containing functional groups, oxidation of silicon,
phosphorus, arsenic, and sulfur, oxidative N-dealkylation,
oxidative O- and S-dealkylation, oxidative deamination, and other
oxidative reactions. [0172] 2. Reductive reactions, such as the
reduction of carbonyl groups, reduction of alcoholic groups and
carbon-carbon double bonds, reduction of nitrogen-containing
functional groups, and other reductive reactions. [0173] 3.
Reactions that do not change the state of oxidation, such as
hydrolysis of esters and ethers, hydrolytic cleavage of
carbon-nitrogen single bonds, hydrolytic cleavage of non-aromatic
heterocyclic compounds, hydration and dehydration at multiple
bonds, new atomic links arising from dehydration reactions,
hydrolytic dehalogenation, removal of halogen-hydrogen molecules,
and other such reactions.
[0174] Carrier prodrugs are medicinal compounds that contain a
transport moiety, which improves, for example, absorption and/or
localized delivery to a site of action. With such a carrier
prodrug, the linkage between the carrier moiety and the transport
moiety is preferably a covalent bond if the prodrug is inactive or
less active than the medicinal compound and if each liberated
transport moiety is not significantly toxic. In the case of
prodrugs in which the transport moiety is intended to improve
absorption, release of the transport moiety should take place
rapidly. In other cases it is desirable to use a moiety that
ensures slow release, such as certain polymers or cyclodextrins.
Such carrier prodrugs are frequently advantageous in the case of
orally administered medicinal substances. Carrier prodrugs can be
used, for example, to achieve one or more of the following goals:
increased lipophilicity, increased duration of pharmacological
actions, increased site specificity, reduced toxicity and fewer
side effects and/or an improvement of the medicinal formulation
(eg, stability, water solubility, suppression of an undesirable
organoleptic or physicochemical property). For example, the
lipophilicity can be increased by esterification of hydroxyl groups
with lipophilic carboxylic acids or of carboxylic acid groups with
alcohols, eg, aliphatic alcohols, as described in Wermuth, The
Practice of Medicinal Chemistry, Chapters 31 and 32, Editor:
Wermuth, Academic Press, San Diego, Calif., 2001.
[0175] Examples of prodrugs are, for example, esters of free
carboxylic acids and S-acyl and O-acyl derivatives of thiols,
alcohols, or phenols, wherein acyl is an R--C(O)-- group.
Pharmaceutically acceptable ester derivatives that are converted to
the parent carboxylic acid under physiological conditions, for
example low-alkyl esters, cycloalkyl esters, low-alkenyl esters,
benzyl esters, monosubstituted or disubstituted lower alkyl esters,
such as the .omega.-(amino, mono- or di-lower alkylamino, carboxyl,
lower alkoxycarbonyl)-lower alkyl esters, the .alpha.-(lower
alkanoyloxy, lower alkoxycarbonyl or di-lower
alkylaminocarbonyl)-lower alkyl esters, such as the
pivaloyloxymethyl ester, are preferred. In addition, amines can be
masked as arylcarbonyloxymethyl substituted derivatives, which are
cleaved in vivo by esterases to liberate the free medicinal
substance and formaldehyde, as described, for example, in
Bundgaard, J. Med. Chem. 2503 (1989). Furthermore, medicinal
substances containing an acid NH group, such as imidazole, imide,
and indole, can be masked with, inter alia, N-acyloxymethyl groups
(cf Bundgaard, Design of Prodrugs, Elsevier (1985). Hydroxyl groups
can be masked as esters and ethers.
[0176] With regard to the close relationship between the presently
described compounds, the compounds in the form of their salts and
prodrugs, all references to the compounds of the invention should
be taken to include the corresponding prodrugs of said
compounds.
[0177] Furthermore, the compounds of the present invention,
including the salts thereof, may also be obtained in the form of
their hydrates or include other solvents as used for
crystallization thereof.
[0178] The compounds of the invention possess valuable
pharmacological properties, because they are aldosterone synthase
inhibitors. As mentioned above, the aldosterone synthase (CYP11B2)
is a mitochondrial cytochrome P450 enzyme that catalyzes the final
three stages of the production of aldosterone in the adrenal
cortex, that is to say, the conversion of 11-deoxycorticosterone to
aldosterone. It has been shown that aldosterone synthase is
expressed in all cardiovascular tissues, such as the heart, in the
umbilical cord, in the mesenteric and pulmonary arteries, in the
aorta, in the endothelium, and in vascular cells. Furthermore, the
expression of the aldosterone synthase is closely correlated with
the production of aldosterone in cells. It has been found that
increasing the aldosterone activity or aldosterone concentration
induces a diversity of diseases, such as congestive heart failure,
cardial or myocardial fibrosis, renal failure, hypertension, or
ventricular arrhythmia.
[0179] Accordingly, the invention relates to the use of a compound
of formula I or II for the treatment of hyperaldosteronism.
[0180] As aldosterone synthase inhibitors, the compounds of the
invention are thus also useful for the prophylaxis of, retardation
of the progression of, or therapy of, diseases or clinical pictures
which respond to an inhibition of the aldosterone synthase or are
characterized by an abnormal aldosterone synthase activity.
Included therein are hypokalaemia, hypertension, renal failure,
particularly chronic renal failure, restenosis, atherosclerosis,
syndrome X, obesity, nephropathy, inflammation, increased collagen
formation, fibrosis, such as cardial or myocardial fibrosis,
remodeling following hypertension, endothelial dysfunction and/or
edema. The compounds of formula (I) are also preferentially
considered in the form of medicinal substances for the treatment of
congestive heart failure, ventricular fibrillation, postmyocardial
infarction syndrome and coronary cardiac diseases.
[0181] In addition, the invention provides the use of the compounds
of the formulas (I) and (II) for the treatment of
hypercortisolismus mediated by 11.beta.-hydroxylase (CYP11B1). This
includes the prophylaxis or retardation of the progression of, or
the therapy of, diseases or clinical pictures such as Cushing's
syndrome, ectopic ACTH formation syndrome, a change in the
adrenocortical mass, primary pigmented nodular adrenocortical
dysplasia (PPNAD), the Carny complex, Anorexia nervosa, chronic
alcoholic intoxication, nicotine and cocaine withdrawal syndromes,
post-traumatic stress syndrome, cognitive impairment following
apoplectic stroke and cortisol-induced mineralocorticoid
excess.
[0182] Another aspect of the invention relates to pharmaceutical
preparations comprising a compound of the invention and a
pharmaceutically acceptable excipient. The pharmaceutical
preparation can be formulated for specific administration routes,
such as oral administration, parenteral administration, and rectal
administration. In addition, the pharmaceutical preparations of the
present invention can be prepared in solid form, including
capsules, tablets, pellets, granules, powders, and suppositories,
or in liquid form, including solutions, suspensions, or emulsions.
The pharmaceutical preparations can be subjected to conventional
pharmaceutical processes, such as sterilization, and/or can contain
conventional inert diluents, slip agents or buffering agents and
also adjuvants such as preserving agents, stabilizing agents,
wetting agents, emulsifiers, and buffers.
[0183] Preferably, the pharmaceutical preparations are in the form
of tablets and gelatin capsules, which contain the active
ingredient together with diluents, eg, lactose, dextrose, sucrose,
mannitol, sorbitol, cellulose and/or glycine; slip agents, eg,
silicon dioxide, talc, stearic acid, their magnesium or calcium
salts, and/or polyethylene glycol; in the case of tablets, also
binding agents, eg, magnesium aluminum silicate, starch paste,
gelatine, tragacanth gum, methyl cellulose, sodium carboxymethyl
cellulose, and/or polyvinylpyrrolidone, if desired also tablet
disintegration agents, eg, starches, agar, alginic acid or its
sodium salt, or effervescent mixtures; and/or absorbents,
stabilizing agents, preserving agents, coloring agents, flavoring
agents, and sweetening agents.
[0184] Tablets may be film coated or provided with a
gastro-resistant coating and comprise a slow release material, such
as glycerol monostearate or glycerol distearate.
[0185] Injectable preparations are preferably aqueous isotonic
solutions or suspensions, and suppositories are advantageously
produced from fatty emulsions or suspensions. These preparations
can be sterilized and/or contain adjuvants, such as preserving
agents, stabilizing agents, wetting or emulsifying agents,
solubilizers, salts for regulation of the osmotic pressure and/or
buffers. They contain approximately from 0.1% to 75%, preferably
approximately from 1% to 50%, of active ingredient.
[0186] Suitable preparations for transdermal application comprise
an effective amount of a compound of the invention together with an
excipient, preferably an absorbable pharmacologically acceptable
solvent, in order to enhance transdermal delivery. Suitable
transdermal devices are all types of plaster. Other preparations
for topical application to the skin or to the eyes, or to the
respiratory passages, comprise aqueous solutions, suspensions,
ointments, creams, gels, and sprayable formulations for, say,
aerosol delivery.
[0187] The compounds of the invention can also be used in anhydrous
pharmaceutical preparations, since water can accelerate the
degradation of some compounds.
[0188] A therapeutically effective amount of the compounds of the
invention can range approximately from 0.1 to 500 mg/kg, preferably
approximately from 1 to 100 mg/kg, depending on the administration
route. The amount of administered active ingredient, ie the dosage
used, depends on the type and severity of the disease being
treated, on the method of administration and the treatment
employed, and on the age and constitutional condition of the
patient and will be adjusted by the physician in charge, according
to general medical expertise, to accommodate the given
situation.
[0189] The pharmaceutical preparations of the invention contain a
therapeutically effective amount of a compound of the invention
either alone or together with another therapeutic agent in suitable
dosage. Such therapeutic agents comprise, for example, active
ingredients to counteract obesity, such as orlistat,
antihypertensive drugs, inotropic agents and hypolipidemic agents,
eg, loop diuretics, such as ethacrynic acid, furosemide, and
torsemide; angiotensine converting enzyme (ACE) inhibitors, such as
benacepril, captopril, enalapril, fosinopril, lisinopril,
moexipril, perinodopril, quinapril, ramipril, and trandolapril;
inhibitors of the Na-K-ATPase membrane pump, such as digoxin;
neutral endopeptidase (NEP) inhibitors; (ACE/NEP inhibitors, such
as omapatrilate, sampatrilate, and fasidotril; angiotensin II
receptor blockers (ARBs), such as candesartane, eprosartane,
irbesartane, losartane, telmisartane, and valsartane, particularly
valsartane; .beta.-receptor blockers, such as acebutolol, atenolol,
betaxolol, bisoprolol, metoprolol, nadolol, propanolol, sotalol,
and timolol; inotropic agents, such as digoxin, dobutamine, and
milrinone; renin inhibitors, such as aliskiren and remikiren;
calcium channel blockers, such as amlodipine, bepridil, diltiazem,
felodipine, nicardipine, nimodipine, nifedipine, nisoldipine, and
verapamil; and 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA)
reductase inhibitors, such as lovastatine, pitavastatine,
simvastatine, pravastatine, cerivastatine, mevastatine,
velostatine, fluvastatine, delvastatine, atorvastatine,
rosuvastatine, and rivastatine. A compound of the present invention
can be administered concurrently with, prior to, or after the other
active ingredient, either separately therefrom by, a different
administration route or together therewith in the same
pharmaceutical formulation.
[0190] Furthermore, the administration can take place
simultaneously, separately, or consecutively.
[0191] The preparation of the compounds of the invention is
explained below.
[0192] The following abbreviations are used:
Ac acetyl BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl Bn
benzyl Boc tert-butyloxycarbonyl Bz benzoyl DIBAL
diisobutylaluminum hydride DMF dimethylformamide DMSO dimethyl
sulfoxide dppf diphenyl-phosphino ferrocene Et ethyl h hours iPr
isopropyl LDA lithium diisopropylamide LHMDS lithium hexamethyl
disilazane mCPBA meta-chloroperbenzoic acid Me methyl min minutes
Ms methanesulfonyl .mu.w microwaves
NBS N-bromosuccinimide
[0193] NMP N-methyl-2-pyrrolidone Pd.sub.2(dba).sub.3
tris(dibenzylideneacetone)dipalladium(0) Pd(dppf)Cl.sub.2
[1.1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)
Pd(PPh.sub.3).sub.4 tetrakis(triphenylphosphine)palladium(0) PG
protective group Ph phenyl Pr propyl R.sub.f retention factor RT
room temperature mp melting point Tf trifluoromethanesulfonyl
Tf.sub.2NPh N-phenyltrifluoromethanesulfonimide
[0194] THF tetrahydrofuran
W Watts
[0195] In Schemes 1-19, R stands collectively for the meanings of
R.sup.3 and R.sup.4 in the above formula (I) at the positions
indicated therein. R' stands collectively for R.sup.5 and R.sup.6
in the meaning of CR.sup.5R.sup.6 in U, X, and Y in formula (I).
R''' in Het-B(OR''') preferably stands for H. R.sup.1 and R.sup.2
have the same meanings as stated with reference to formula (I). Het
in Schemes 1-19 is as defined in formula (I).
[0196] Compounds of the general structure (I) having a quinolinone
or quinoline thione skeletal structure can be produced from
anilines according to Scheme 1. For this purpose, acylation is
first carried out using an .omega.-chlorocarboxylic acid chloride
in acetone (Step a) followed by an intramolecular Friedel Crafts
alkylation in an AlCl.sub.3/NaCl melt at 150.degree. C. (Step b).
The introduction of a suitable leaving group is then carried out
either via the formation of a triflate (Step c) or by
regioselective bromination by means of NBS (Step d). The resulting
central intermediate stage can be derivatized by N-alkylation (Step
g) and/or electrophilic substitution on the aromatic compound (Step
e). The target compounds are obtained via transition metal
catalyzed cross coupling (for example Suzuki coupling) (Step f) and
can be derivatized with Lawesson's reagent (Step h) to form the
corresponding thio analogues.
[0197] The substituted 4-aminophenols used for the syntheses
according to Scheme 1 are commercially available when R denotes
2-Me [CAS: 2835-96-3], 3-Me [CAS: 2835-99-6], 2-iPr [CAS:
16750-66-6], 3-iPr [CAS: 82744-61-6], 3-Pr [CAS: 226084-99-7], 3-Et
[CAS: 61638-00-4], 2-F [CAS: 399-96-2], 3-F [CAS: 399-95-1], 2-Cl
[CAS: 3964-52-1], 3-Cl [CAS: 17609-80-2], 2-OH [CAS: 13047-04-6],
3-OH [CAS: 34781-86-7], 2-OMe [CAS: 52200-90-5], 3-OMe [CAS:
61638-01-5].
[0198] Other substituted 4-aminophenols can be synthesized
according to synthesis instructions described in the literature
when R denotes 3-Et [CAS: 61638-00-4], J. Am. Chem. Soc. 1941, 63,
308-11; 2-Et [CAS: 178698-88-9], 2-Pr [CAS: 855397-55-6], U.S. Pat.
No. 2,533,203; 2-CF.sub.3 [CAS: 1535-76-8], 3-CF.sub.3 [CAS:
445-04-5], WO 2007097937, J. Org. Chem. 1962, 27, 4660-2; 2-OEt
[CAS: 55483-70-0], 3-OEt [CAS: 139444-58-9], J. Am. Chem. Soc.
1919, 41, 1450-72; 2-OPh [CAS: 669092-25-5], J. Org. Chem. 1950,
15, 1108-12; 3-OPh [CAS: 669092-27-7], U.S. Pat. No. 2,525,515;
2-OBn [CAS: 106131-28-6], J. Med. Chem. 1995, 38, 4157-60;
2-Cyclopropyl [CAS: 947607-29-6], WO2007097937.
[0199] The substituted anilines used for the syntheses according to
Scheme 1 are commercially available when R denotes 2-Me [CAS:
95-53-4], 3-Me [CAS: 108-44-1], 2-Et [CAS: 578-54-1], 3-Et [CAS:
587-02-0], 2-Pr [CAS: 1821-39-2], 2-iPr [CAS: 649-28-7], 3-iPr
[CAS: 5369-16-4], 2-CF.sub.3 [CAS: 88-17-5], 3-CF.sub.3 [CAS:
98-16-8], 2-Bn [CAS: 28059-64-5], 3-Bn [CAS: 61424-26-8],
2-Cyclopropyl [CAS: 3158-73-4], 3-Cyclopropyl [CAS: 485402-64-0],
2-F [CAS: 348-54-9], 3-F [CAS: 372-19-0], 2-Cl [CAS: 95-51-2], 3-Cl
[CAS: 108-42-9], 2-OH [CAS: 95-55-6], 3-OH [CAS: 591-27-5], 2-OMe
[CAS: 90-04-0], 3-OMe [CAS: 536-90-3], 2-OEt [CAS: 94-70-2], 3-OEt
[CAS: 621-33-0], 2-OPh [CAS: 2688-84-8], 3-OPh [CAS: 3586-12-7],
2-SPh [CAS: 1134-94-7], 2-NH.sub.2 [CAS: 95-54-5], 3-NH.sub.2 [CAS:
108-45-2]. Other substituted anilines can be synthesized according
to synthesis instructions described in the literature when R
denotes, for example, 3-SPh [CAS: 3985-12-4], J. Am. Chem. Soc.
2006, 128, 2180-81.
##STR00004##
[0200] The synthesis of the pyrrolo or pyrido quinolinones or
pyrrolo or pyrido thiones (Scheme 2) starting from indolines (n=1)
or tetrahydroquinolines (n=2) is carried out in an analogous
manner. For this purpose, in this case also, acylation is first
carried out using an .omega.-chlorocarboxylic acid chloride in
acetone (Step a) followed by an intramolecular Friedel Crafts
alkylation in an AlCl.sub.3/NaCl melt at 150.degree. C. (Step b).
Bromination with NBS in DMF at 0.degree. C. yields selectively the
para-substituted product (Step c). This can be converted to a
boronic-acid ester by reaction with bis(pinacolato)diborone under
palladium catalysis (Step d). The heterocycle is then introduced
via Suzuki coupling (Het) (Step e), either by reaction of the
bromide with a heterocyclic boronic acid or by reaction of the
boronic acid ester with a heterocyclic halide or triflate. The
resulting oxo compounds can be derivatized to the corresponding
thio analogues with Lawesson's reagent (Step f).
[0201] The substituted indolines used for the syntheses according
to Scheme 2 (n=1) are commercially available when R denotes H [CAS:
496-15-1], 4-Me [CAS: 62108-16-1], 4-CF.sub.3 [CAS: 905274-07-9],
4-F [CAS: 552866-98-5], 4-CN [CAS: 885278-80-8], 4-Cl [CAS:
41910-64-9], 4-Br [CAS: 86626-38-2], 4-OH [CAS: 85926-99-4], 4-OMe
[CAS: 7555-94-4], 4-OEt [CAS: 220657-56-7], 4-OPh [CAS:
930790-14-0], 4-NH.sub.2 [CAS: 52537-01-6], 4-CO.sub.2H [CAS:
175647-03-7], 4-NO.sub.2 [CAS: 84807-26-1], 6-Me [CAS: 86911-82-2],
6-Et [CAS: 162716-49-6], 6-Pr [CAS: 172078-24-6], 6-CF.sub.3 [CAS:
181513-29-1], 6-F [CAS: 2343-23-9], 6-CN [CAS: 15861-35-5], 6-Cl
[CAS: 52537-00-5], 6-Br [CAS: 63839-24-7], 6-OMe [CAS: 7556-47-0],
6-OPh [CAS: 930791-17-6], 6-NH.sub.2 [CAS: 15918-79-3], 6-CO.sub.2H
[CAS: 15861-37-7], 6-NO.sub.2 [CAS: 19727-83-4], or 6-iPr [CAS:
122299-59-6].
[0202] Other substituted indolines (n=1) can be synthesized
according to synthesis instructions described in the literature
when R denotes, for example, 4-Et [CAS: 127693-34-9], Arch. Pharm.
1990, 323, 145-155; 6-Pr [CAS: 172078-24-9], WO 9523141; 6-OH [CAS:
4770-37-0], U.S. Pat. No. 5,256,799, Tetrahedron Lett. 1986, 27,
4565-68; 6-OEt [CAS: 37865-90-0], Heterocycles 1998, 48, 2481-84;
6-0iPr [CAS: 37865-92-2], DE 2843192; 4-F [CAS: 552866-98-5],
Bioorg. Med. Chem. Lett. 2002, 12, 3105-09; 4-OPh [CAS:
930790-14-0], US 2007072897; or 6-OPh [CAS: 930791-17-6], US
2007072897.
[0203] Other substituted indolines (n=1) can be produced by
regioselective reduction of the heterocyclic five membered ring of
the correspondingly substituted indoles with boron hydride reagents
such as NaBH.sub.4 or NaBH.sub.4CN according to synthesis
instructions described in the literature (Bioorg. Med. Chem. Lett.
2002, 12, 3105-09; J. Med. Chem. 2004, 47, 5451-66; Synth. Commun.
1983, 13, 489-93; Bioorg. Med. Chem. 2006, 14, 2005-21; Chem.
Commun. (Cambridge, UK) 2005, (29), 3664-66).
[0204] The substituted tetrahydroquinolines used for the syntheses
according to Scheme 2 (n=2) are commercially available when R
denotes H [CAS: 635-46-1], 5-iPr [CAS: 777013-12-4], 5-CN [CAS:
939758-72-2], 5-CF.sub.3 [CAS: 939758-74-4], 5-CO.sub.2H [CAS:
114527-54-7], 5-NH.sub.2 [CAS: 36887-98-6], 5-F [CAS: 345264-61-1],
7-Me [CAS: 58960-03-5], 7-iPr [CAS: 746560-03-5], 7-CF.sub.3 [CAS:
450-62-4], 7-CN [CAS: 939758-76-6], 7-CO.sub.2H [22048-88-0],
7-NO.sub.2 [CAS: 30450-62-5], 7-NH.sub.2 [CAS: 153856-89-4], 7-OH
[CAS: 58196-33-1], 7-F [CAS: 939758-75-5].
[0205] Other substituted tetrahydroquinolines (n=2) can be
synthesized according to synthesis instructions described in the
literature when R denotes, for example, 5-NO.sub.2 [CAS:
39217-91-9], WO 2007052843, Bioorg. Med. Chem. Lett. 2006, 16,
4533-36; 5-OH [CAS: 61468-43-7], WO 2003011862, Tetrahedron Lett.
1986, 27, 4565-68; 5-OMe [CAS: 30389-37-8], JP 55040616, Chemistry
& Industry (London) 1970, 45, 1435; 5-OPh [CAS: 860204-04-2],
Yakugaku Zasshi 1952, 72, 905-08; 5-Cl [CAS: 72995-16-5], JP
55040616, US 2004116388; 5-Br [CAS: 114744-50-2], New Journal of
Chemistry 1987, 11, 605-09; 7-OMe [CAS: 19500-61-9], U.S. Pat. No.
5,696,133, U.S. Pat. No. 5,696,130, Bioorg. Med. Chem. Lett. 2002,
12, 387-90; 7-OPh [CAS: 874498-69-8], Yakugaku Zasshi 1952, 72,
905-08; 7-Cl [CAS: 90562-35-9], US 2004116388; 7-Br [CAS:
114744-51-3], New Journal of Chemistry 1987, 11, 605-09, WO
9902502.
[0206] Other substituted tetrahydroquinolines (n=2) can be produced
by regioselective reduction of the heterocyclic 6-ring of
appropriately substituted quinolines. Preferably used reduction
systems for this purpose are elemental hydrogen or boron hydrides
used together with a transition metal catalyst such as Pd, Pt, In,
Ni, Rh (Organic & Biomolecular Chemistry 2006, 4, 2529-31; J.
Am. Chem. Soc. 2005, 127, 2125-35; Synlett 2004, (15), 2827-29; J.
Org. Chem. 2004, 69, 2871-73; Advanced Synthesis &Catalysis
2003, 345, 275-79; Tetrahedron Lett. 2001, 42, 2763-66; Synlett
1998, (9), 1029-30).
##STR00005##
[0207] In particular, 3,5-disubstituted pyridines carrying, in
addition to the pyrrolo or pyrido quinolinone or pyrrolo or pyrido
thione skeletal structure another sp.sup.2-hybridized substituent
(eg, aryl, heteroaryl) can be produced according to Scheme 3. The
reaction sequence takes place in this case via two consecutive
Suzuki couplings (Steps a and b). The resulting oxo compounds can
be derivatized to the corresponding thio analogues with Lawesson's
reagent (Step c).
##STR00006##
[0208] Pyrrolo or pyrido quinolinones or pyrrolo or pyrido thiones
in which the heterocycle is linked to the skeletal structure via an
alkyl or alkanoyl linker are produced as depicted in Scheme 4 or
Scheme 5. The starting compounds used are the tricyclic
intermediate stages described in Scheme 2.
[0209] In the case of 1-imidazoles (Scheme 4), an alkylcarbonyl or
arylcarbonyl substituent is first of all introduced by selective
Friedel Crafts acylation (Step a), followed by reduction with
NaBH.sub.4 in methanol (Step b). The heterocycle is then introduced
by reaction with thionyl-bis-imidazole in THF (Step c). The
resulting oxo compounds can be derivatized to the corresponding
thio analogues with Lawesson's reagent (Step d). In this scheme,
R'' stands for R.sup.8 or R.sup.9 in the meaning of
A=CR.sup.8R.sup.9 in formula (I).
##STR00007##
[0210] In the synthesis of other heterocyclic compounds of the
general structure (I) (Scheme 5), the introduction of the
heterocycle is carried out via Friedel Crafts acylation (Step a).
The resulting dioxo compounds can be derivatized further to form
secondary or tertiary alcohols by reduction or the Grignard
reaction (Step b) and subsequent reduction to alkanes (Step d), and
also by thionation with Lawesson's reagent (Step c). In this
scheme, R' stands for R.sup.8 or R.sup.9 in the meaning of
A=CR.sup.8R.sup.9 in formula (I).
##STR00008##
[0211] The carbonyl compounds obtained after introduction of the
heterocycle via Friedel Crafts acylation (Step a, Scheme 5) can be
converted to the corresponding cyclopropyl derivatives in another
derivatization involving Wittig olefination followed by
cyclopropanation via the Simmons Smith reaction (Scheme 5a).
##STR00009##
[0212] The synthesis of other compounds of this invention having a
pyrrolo or pyrido quinolinone structure or a pyrrolo or pyrido
thione structure and a thiadiazine indole dioxide structure (Scheme
6) starts from cyano or cyanoalkyl substituted indolines (n=1) or
tetrahydroquinolines (n=2) via reduction (Step a) followed by
cyclization with the introduction of an SO.sub.2 group (Step b) or
a CO group (Step c). There then follows, for the production of the
pyrrolo or pyrido quinolinones or pyrrolo or pyrido thiones, the
described synthesis sequence consisting of bromination, Suzuki
coupling, nucleophilic derivatization of the quinazoline nitrogen,
and thionation using Lawesson's reagent (Steps d to g). In this
scheme, R.sup.7 has the meanings stated with reference to the
compounds of formula (I).
[0213] The cyano-substituted indoline (n=1, m=0, R'=H, R=H) used
for the syntheses according to Scheme 6 is synthesized according to
synthesis instructions described in the literature: [CAS:
115661-82-0], U.S. Pat. No. 5,380,857, EP 257583. Other substituted
7-cyanoindolines (n=1, m=0, R'=H) are synthesized according to the
syntheses described in the literature for Scheme 2 from the
correspondingly substituted indoles when R denotes, for example,
4-OMe [CAS: 389628-45-9], WO 2002004440, US 2003069245; or R
denotes 4-F [CAS: 313337-33-6], commercially available; or R
denotes 6-NO.sub.2 [CAS: 354807-15-1], Heterocycles 2001, 55,
1151-59.
[0214] Other substituted 7-cyanoalkylindolines (n=1, m=1, R'=0) are
synthesized by regioselective reduction of the corresponding
commercially available indoles according to the syntheses described
in the literature for Scheme 2 when, for example: R denotes H [CAS:
8299-98-2], R denotes 4-F [CAS: 1000516-43-7], or R denotes 4-OMe
[CAS: 1000558-59-7]. 7-Aminoindoline [CAS: 2759-12-8] and
7-methylaminoindoline [CAS: 2580-93-0], (J. Am. Chem. Soc. 1966,
88, 4061-68), are directly converted according to Steps b and
c.
[0215] The 8-alkylamino substituted tetrahydroquinolines used in
Steps b and c according to Scheme 6 (n=2, R, R'=H, m=0, CAS:
148287-05-2) and (n=2, R, R'=H, m=1, CAS: 148287-05-3) are
commercially available or are obtainable by syntheses described in
the literature (FR 2675801, J. Am. Chem. Soc. 1966, 88,
4061-68).
##STR00010##
[0216] The synthesis of oxazino indolones or oxazino quinolinones
(Scheme 7) is carried out in a similar manner starting from carboxy
substituted indolines (n=1) or tetrahydroquinolines (n=2).
Following reduction to the alcohol starting from the carbonyl
compound (ketone or aldehyde), wherein R' is alkyl or H
respectively) or the carboxyl compound (carboxylic acid or
carboxylate wherein R' is OH or OMe or OEt respectively) by means
of a suitable reducing agent (eg, NaBH.sub.4, BH.sub.3.THF or
LiAlH.sub.4) or a Grignard reaction with a carbonyl compound
(ketone or aldehyde, wherein R' is alkyl or H) (all Step a) there
follows the aforementioned synthesis sequence (Steps b to e).
[0217] The 8-carboxy substituted indolines (n=1, m=0) used for the
syntheses according to Scheme 7 are commercially available when
R=H, R'=H [143262-21-9], or R=6-F, R'=H [603310-02-7], R=H, R'=Me
[104019-19-4], or R=H, R'=OMe [112106-91-9]. The 8-carboxy indoline
(R=H, R'=OH, CAS: 15861-40-2) is obtainable according to synthesis
instructions described in the literature (WO 2003103398, J. Med.
Chem. 1996, 39, 4692-03). The 8-carboxy substituted indolines
extended by a methylene group (n=1, m=1) are, in the case of
carboxylic acid (R'=OH, R=H, CAS: 2580-92-9) and of the
corresponding methyl ester (R'=OMe, R=H, CAS: 7633-52-5), obtained
by synthesis described in the literature (J. Am. Chem. Soc. 1966,
88, 4061-68). The corresponding keto compound (R=H, R'=Me, CAS:
7633-52-5) is commercially available.
[0218] The 8-carboxy substituted tetrahydroquinolines used for the
syntheses according to Scheme 7 (n=2, m=0) are obtainable via
syntheses described in the literature: R'=H, R=H [CAS: 69906-07-6],
Synthesis 1979, 2, 99-100; R'=OMe, R=H [CAS: 477532-02-8], WO
2003022785, J. Org. Chem. 2002, 67, 7890-93; R'=OMe, R=5-F [CAS:
928839-61-6], WO 2007028789; R'=OMe, R=5-Br [CAS: 928839-65-0], WO
2007028789. The keto compound (R'=Me, R=H, CAS: 890093-80-8) is
commercially available, as is the 8-carboxy substituted
tetrahydroquinoline extended by a methylene group (n=2, m=1, R'=OH,
R=H, CAS: 933727-44-7).
##STR00011##
[0219] Pyrroloquinoxalinones and oxazino and thiazino indolones are
synthesized starting from U'-functionalized (wherein U' is
NH.sub.2, NO.sub.2, OH, SH) indolines (n=1), or
tetrahydroquinolines (n=2) (Scheme 8). For this purpose, acylation
with an .omega.-chlorocarboxylic acid chloride or sulfonic acid
chloride (Step a) is first carried out. This is followed by
cyclization via an intramolecular S.sub.N reaction (Step b). A
heterocycle is then introduced via Pd catalyzed cross coupling
(Step c). The groups X', U', U and Z depicted in Scheme 8 can be
further modified chemically prior to or after each Step a, b, or c
eg, from X'=OH to X'=OTf, from U'=NO.sub.2 to U'=NH.sub.2, from
U=NH to U=NR.sup.7, from U=S to U=SO.sub.(2), or from Z=CO to Z=CS.
Reactive functional groups such as --OH, --NH.sub.2, --SH should be
optionally protected during the synthesis with suitable protective
groups described in the literature and should be deprotected at a
suitable moment. U and Z have the meanings stated with reference to
formula (I).
[0220] The substituted indolines used for the syntheses according
to Scheme 8 (n=1) are synthesized according to synthesis
instructions described in the literature: (U'=OH, X'=H, R=H, CAS:
4770-38-1, Tetrahedron Lett. 2005, 46, 1021-22), (U'=SH, X'=H, R=H,
CAS: 72696-18-5, JP 54132597), (U'=NH.sub.2, X'=Br, R=H, CAS:
503621-32-7, WO 2003027090) or are commercially available, (U'=OMe,
X'=H, R=H, CAS: 334986-38-1), (U'=NH.sub.2, X'=H, R=H, CAS:
2759-12-8), (U'=OMe, X'=OMe, R=H, CAS: 82260-13-7). Other
substituted indolines (n=1) are synthesized by regioselective
reduction of the corresponding commercially available indoles
according to the synthesis instructions described in the literature
for Scheme 2.
[0221] The substituted tetrahydroquinolines used for the syntheses
according to Scheme 8 (n=2) are synthesized according to synthesis
instructions described in the literature: (U'=SH, X'=H, R=H, CAS:
21570-31-0, J. Org. Chem. 1963, 28, 2581-7), (U'=NH.sub.2, X'=Br,
R=H, CAS: 859959-07-2, Berichte der Deutschen Pharmazeutischen
Gesellschaft 1911, 20, 183-200), (U'=NH.sub.2, X'=OMe, R=H, CAS:
19279-83-5, US 2007032469, EP 146370) or are commercially available
(U'=OH, X'=H, R=H, CAS: 6640-50-2), (U'=OMe, X'=OMe, R=H, CAS:
953906-79-1), (U'=OMe, X'=H, R=H, CAS: 53899-17-5).
##STR00012##
[0222] The indolines used for the syntheses can be obtained by
reduction (eg, with sodium cyanoboron hydride) of the corresponding
indoles. Compounds of the general formula (I) can be obtained by
methods described in the literature, including in an
enantiomerically pure state, for example, by salt formation with
optically active acids (eg, (+)- or (-)-mandelic acid followed by
separation of the diastereoisomeric salts by fractional
crystallization or by derivatization with a chiral auxiliary
followed by separation of the diastereoisomeric products by
chromatography and/or recrystallization. The absolute configuration
of freshly generated stereocenters can be determined by
radiographic methods.
[0223] Syntheses of other heterocycles of the general structure (I)
can be carried out as shown in the schemes listed below (Schemes 9
to 18). In Schemes 9, 10, and 12, R stands collectively for
R.sup.2, R.sup.3, and R.sup.4 in formula (I) at the positions
stated.
[0224] The substituted methyl 2-aminobenzoates (methyl
anthranilates) used for the syntheses according to Scheme 9 and
having a leaving group at position 5 (X'=Br) are commercially
available or are synthesized according to synthesis instructions
described in the literature: R=H [CAS: 52727-57-8], commercially
available; R=4-iPr [CAS: 1000018-13-2], commercially available;
R=3-Me [CAS: 206548-14-3], commercially available; R=3-Br [CAS:
606-00-8], commercially available; R=6-Cl [CAS: 943138-46-3],
Bioorg. Med. Chem. Lett. 2007, 17, 2817-22; R=6-Me [CAS:
573692-58-7], Bioorg. Med. Chem. Lett. 2007, 17, 2817-22; WO
2004108672; R=6-OMe [CAS: 681247-48-3], Bioorg. Med. Chem. Lett.
2007, 17, 2817-22; WO2004033419; R=6-OEt [CAS: 681247-12-1],
Bioorg. Med. Chem. Lett. 2007, 17, 2817-22; WO2004033419;
R=6-NO.sub.2 [CAS: 90050-54-7], Tetrahedron 1963, 19, 1911-17;
R=4-NO.sub.2 [CAS: 174566-52-0], WO 9532205; R=4-OMe [CAS:
169044-96-6], WO 9518097; R=3-Cl [CAS: 101080-26-6], Zhurnal
Oshchei Khimii 1957, 27, 1554-57; R=3-NO.sub.2 [CAS: 636581-61-8],
WO 2007148093; WO 2006099379; R=3-OMe [CAS: 115378-21-7], WO
2008019372; WO 2005113509.
[0225] Other substituted methyl anthranilates (X'=OMe) used, which
are first of all derivatized by removal of the methyl group and
conversion of the hydroxyl function by means of standard methods to
the corresponding triflate, are obtainable according to syntheses
described in the literature when R is 4-F [CAS: 159768-51-1],
Tetrahedron Lett. 2005, 46, 7381-84; EP 635498; EP 602851; or R is
4-Cl [CAS: 181434-36-8], WO 9622991; U.S. Pat. No. 5,792,767.
##STR00013##
[0226] The substituted 2-nitrobenzonitriles used for the syntheses
according to Scheme 10 and having a leaving group in position 5
(X'=Br, Cl, OTf) are commercially available or are synthesized
according to synthesis instructions described in the literature:
X'=Br, R=H [CAS: 89642-50-2], J. Org. Chem. 1961, 26, 4967-74; J.
Am. Chem. Soc. 1960, 82, 3152-57; X'=Br, R=4-F [CAS: 927392-00-5],
J. Am. Chem. Soc. 1960, 82, 3152-57; JP 2007204458; X'=Br, R=6-Me
[CAS: 110127-08-7], U.S. Pat. No. 4,677,219; X'=Cl, R=4-F [CAS:
906559-47-5], WO 2006088919; X'=Cl, R=4-Me [CAS: 97113-40-1], J.
Med. Chem. 1985, 28, 1387-93; X'=OH, R=4-Me [CAS: 873999-89-4],
commercially available; X'=OH, R=6-NO.sub.2 [CAS: 861604-57-1],
commercially available.
##STR00014##
[0227] The ortho-fluoro substituted nitrobenzenes used for the
syntheses according to Scheme 11 and having a leaving group in
position 4 are commercially available: X'=Br [CAS: 321-23-3]; X'=Cl
[CAS: 70037-8]; X'=OH [CAS: 394-41-2].
##STR00015##
[0228] The substituted 5-bromo-2-aminobenzonitriles used for the
syntheses according to Scheme 12 are commercially available or are
synthesized according to synthesis instructions described in the
literature: R=H [CAS: 39263-32-6]; R=3-Cl [CAS: 914636-86-5];
R=3-Br [CAS: 68385-95-5]; R=3-Cl/6-F [CAS: 1000577-60-5]; R=4-Cl
[CAS: 671795-60-1]; R=6-F [CAS: 845866-92-4]; R=3-CF.sub.3 [CAS:
1000571-53-8]; all commercially available. R=3-OMe [CAS:
176718-54-0], Chem. Pharm. Bull. 1996, 44, 547-51; R=3-CN [CAS:
40249-43-2], JP 59134770, DE 2137719, GB 1411913; R=3-CN/4-Me [CAS:
88817-30-5], U.S. Pat. No. 4,582,898, DE 3220117; R=4-F/6-Me [CAS:
927392-19-6], WO 2007020936; R=6-Me [CAS: 110127-09-8], WO 9418980;
R=6-Cl [CAS: 159020-87-8], WO 9418980.
##STR00016##
[0229] The 4-bromo-1-methoxy-2-nitrobenzene [CAS: 771583-12-1] used
for the syntheses according to Scheme 13 is synthesized according
to synthesis instructions described in the literature (WO
2008014822). 4-Chloro-1-methoxy-2-nitrobenzene [CAS: 109319-85-9]
is commercially available.
##STR00017##
[0230] The substituted 3,4-dihydroquinolinones (U=CH.sub.2, Z=CO)
used for the syntheses according to Scheme 14 and having a leaving
group (X'=OTf, Br, Cl) in position 6 are synthesized according to
synthesis instructions described in the literature or are
commercially available: (X'=Br, R=H, CAS: 3279-90-1), (X'=OH, R=H,
CAS: 54197-66-9), (X'=Br, R=8-NO.sub.2, CAS: 858213-76-0), (X'=Cl,
R=7-Me, CAS: 116936-84-6), all commercially available; (X'=Br,
R=8-Me, CAS: 1872-69-1, FR 1531330, US 330502, GB1046226); (X'=Br,
R=5-OH, CAS: 148934-11-6, Organic Preparation & Procedures
International 1993, 25, 223-28); (X'=Cl, R=7-OH, CAS: 72565-97-0,
U.S. Pat. No. 4,482,560, DE 3034237, DE 2912105); (X'=Cl, R=7-OMe,
CAS: 72565-96-9, U.S. Pat. No. 4,482,560, DE 3034237, DE 2912105);
(X'=Cl, R=7-NH.sub.2, CAS: 813425-54-6, WO 2004110986); (X'=Cl,
R=8-Me, CAS: 2004-25-3, FR 1531330, DE 1289051); (X'=OH, R=8-F,
CAS: 143268-82-0, J. Med. Chem. 1992, 35, 3607-12); (X'=OH, R=8-Cl,
CAS: 119729-98-5, J. Heterocycl. Chem. 1988, 25, 1279-81); (X'=OH,
R=7-Br, CAS: 71100-14-6, JP 54032481); (X'=OH, R=7-OMe, CAS:
68360-27-0, J. Chem. Soc. Perkin Trans. 1 1978, 5, 440-46); (X'=OH,
R=7-NO.sub.2, CAS: 359864-62-3, Chem. Pharm. Bull. 2001, 49,
822-29); (X'=OH, R=7-CO.sub.2H, CAS: 59865-01-9, JP 51016679);
(X'=OH, R=5-Cl, CAS: 69592-12-7, DE 2825048).
[0231] The substituted 2H-benzo[b][1,4]-oxazin-3(4H)-ones used for
the syntheses according to Scheme 14 (U=0, Z=CO) and having a
leaving group (X'=Br, OTf) in position 7 are synthesized according
to synthesis instructions described in the literature or are
commercially available: (X'=OH, R=H, CAS: 67193-97-9, WO
2006027684); (X'=OMe, R=5-Cl, CAS: 138035-69-5, Heterocycles 1991,
32, 1681-85); (X'=OMe, R=H, CAS: 6529-94-8, J. Med. Chem. 1987, 30,
580-83);
[0232] The substituted 2H-benzo[b][1.4]-thiacin-3(4H)-ones used for
the syntheses according to Scheme 14 (U=S, Z=CO) and having a
leaving group (X'=Br, OTf) in position 7 are synthesized according
to synthesis instructions described in the literature or are
commercially available: (X'=Br, R=H, CAS: 90814-91-8), (X'=OH, R=H,
CAS: 91375-75-6), (X'=OMe, R=H, CAS: 22726-30-3), all commercially
available.
[0233] The substituted cyclic sulfonamides (U=CH.sub.2, Z=SO.sub.2)
used for the syntheses according to Scheme 14 and having a leaving
group (X'=Br, OTf) in position 6 are synthesized according to
synthesis instructions described in the literature: (X'=Br, R=H,
CAS: 3279-87-6, U.S. Pat. No. 3,303,190, J. Org. Chem. 1965, 30,
3163-66); (X'=OMe, R=H, CAS: 93427-20-4, J. Org. Chem. 1984, 49,
9124-39).
##STR00018##
[0234] The bicyclic starting compounds used for the syntheses
according to Scheme 15: 3,4-dihydroquinolinone (U=CH.sub.2), CAS:
553-03-7; 2H-benzo[b][1,4]oxazin-3(4H)-on (U=O), CAS: 5466-88-6;
2H-benzo[b][1,4]thiazin-3(4H)-one (U=S), CAS: 5325-20-2;
benzo[e][1,4]oxazepin-2(1H,3H,5H)-on (U=CH.sub.2O), CAS: 3693-08-1;
4,5-dihydro-1H-benzo[b]azepin-2(3H)-on (U=CH.sub.2--CH.sub.2), CAS:
4424-80-0 are commercially available.
Benzo[e][1,4]thiazepin-2(1H,3H,5H)-one (U=CH.sub.2S) is synthesized
according to synthesis instructions described in the literature
(CAS: 1128-46-7, J. Org. Chem. 1965, 30, 3111-14).
[0235] The tricyclic starting compounds used for the syntheses
according to Scheme 15 are synthesized according to synthesis
instructions described in the literature or are commercially
available: U=CH.sub.2, CAS: 57369-32-1, commercially available;
U=O, CAS: 67548-65-6, JP 54132597, JP 53062829; U=S, CAS:
72696-16-3, JP 54132597; (U=CH.sub.2--CH.sub.2), CAS: 221692-31-5,
Bioorg. Med. Chem. Lett. 2003, 13, 701-04).
##STR00019##
[0236] The 5-bromo-2-nitrobenzaldehyde used for the syntheses
according to Scheme 16 (CAS: 20357-20-4) is commercially available
or is readily available according to the synthesis described in the
literature (Org. Lett. 2003, 5, 2251-53). 2-Nitrobenzaldehyde (CAS:
552-89-6) is likewise commercially available.
##STR00020##
[0237] The 4-chloro-2-methoxy-1-nitrobenzene (X'=Cl) used for the
syntheses according to Scheme 17, CAS: 6627-53-8 is commercially
available. The 4-bromo-2-methoxy-1-nitrobenzene (X'=Br), CAS:
103966-66-1 is synthesized according to synthesis instructions
described in the literature (WO 2006040182, WO 2002036588, WO
2001032631), likewise 3-methoxy-4-nitrophenol (X'=OH, CAS:
16292-95-8; Org. Lett. 2008, 10, 997-1000).
[0238] The starting compounds used for the syntheses according to
Scheme 17--4-bromo-2-fluoro-1-nitrobenzene (X'=Br, CAS: 321-23-3),
4-chloro-2-fluoro-1-nitrobenzene (X'=Cl, CAS: 700-37-8), and
3-fluoro-4-nitrophenol (X'=OH, CAS: 394-41-2)--are commercially
available.
##STR00021##
[0239] The (5-chloro-2-nitrophenyl)methanol [CAS: 73033-58-6] used
for the syntheses according to Scheme 18 is commercially available.
The diamino compound required for Step g is synthesized as
described in Scheme 12.
##STR00022##
[0240] The starting compounds used for the syntheses according to
Scheme 19 are synthetic or commercially available, as described in
the syntheses illustrated above (cf Schemes 1, 2, 6, 7, 8, 14, 15
and 16).
##STR00023##
[0241] Those skilled in the art are conversant with the precise
reaction conditions of the reactions illustrated in Schemes 1-19,
which are all analogy processes. Further details are disclosed in
the following examples.
[0242] Reactive functional groups present in the starting compounds
or in intermediates formed during the synthesis (inter alia,
alcohols, thiols, amines, carboxylic acids) should be protected,
depending on the respective reaction conditions, using protective
groups that are conventionally used in organic syntheses, as
described in the literature. At suitable moments during the
syntheses, the introduced protective groups are removed by the use
of reaction conditions as described in the literature, (cf, eg,
Theodora W. Greene, Peter G. M. Wuts, Protective Groups in Organic
Synthesis (3rd Edition, John Wiley & Sons Inc. 1999) and Philip
J. Kocienski, Protecting Groups (3rd Edition, Georg Thieme Verlag
Stuttgart, New York 2005).
[0243] The reaction products can be converted, by methods known to
the person skilled in the art, to stable salts thereof, preferably
HCl salts or other pharmaceutically acceptable salts thereof.
EXAMPLES
[0244] The following examples illustrate the present invention and
are not intended to limit the scope thereof.
[0245] Chemical and analytical methods. Melting points were
measured on a Mettler FP1 melting point apparatus and are
uncorrected. .sup.1H-NMR and .sup.13C-NMR were recorded on a Bruker
DRX-500 (500 MHz) instrument. Chemical shifts are given in parts
per million (ppm), and tetramethylsilane (TMS) was used as internal
standard for spectra obtained in DMSO-d.sub.6 and CDCl.sub.3. All
coupling constants (J) are given in hertz. Mass spectra (LC/MS)
were measured on a TSQ Quantum (Thermo Electron Corporation,
Dreireich, Germany) instrument with a RP18 100-3 column (Macherey
Nagel, Duren, Germany) and with water/acetonitrile mixtures as
eluents. Reagents were used as obtained from commercial suppliers
without further purification. Solvents were distilled before use.
Dry solvents were obtained by distillation from appropriate drying
reagents and stored over molecular sieves. Flash chromatography was
performed on silica gel 40 (35/40-63/70 .mu.M) with hexane/ethyl
acetate or dichloromethane/methanol mixtures as eluents, and the
reaction progress was determined by thin-layer chromatography
analyses on Alugram SIL G/UV254 (Macherey-Nagel). Visualization was
accomplished with UV light and KMnO.sub.4 solution. All microwave
irradiation experiments were carried out in a CEM-Discover monomode
microwave apparatus.
[0246] The following are the structural formulae of the compounds
synthesized in the Examples:
##STR00024## ##STR00025## ##STR00026## ##STR00027## ##STR00028##
##STR00029## ##STR00030## ##STR00031## ##STR00032## ##STR00033##
##STR00034## ##STR00035##
Synthesis of the Starting Materials and Intermediates
General Procedure I: Bromination
[0247] To a solution of the corresponding substituted
tetrahydro-1H-quinolin-2-one (0.75 mol, 1 equivalent) in DMF (50
mL) was added dropwise a solution of NBS (0.79 mol, 1.05
equivalents) in DMF (20 mL) under N.sub.2 in an ice bath. Then the
reaction mixture was stirred at 0.degree. C. for 10 to 15 hours
before dilution with water. The mixture was extracted 3 times with
ethyl acetate, then the combined organic layers were washed with
brine, dried over MgSO.sub.4 and the solvents were removed in
vacuo. The solid residues were purified by flash chromatography on
silica gel (hexanes/ethyl acetate) to give the desired product.
Synthesis Example 1
6-Bromo-3,4-dihydro-1H-quinolin-2-one
[0248] To a solution of 3,4-dihydro-1H-quinolin-2-one (10.0 g, 67.9
mmol) in 100 ml dry DMF was added dropwise a solution of
N-bromosuccinimide (12.7 g, 71.3 mmol) in 150 ml dry DMF at
0.degree. C. The mixture was stirred at 0.degree. C. for 2 h, then
400 ml water was added and the solution was extracted with ethyl
acetate (3.times.150 ml). The organic phase was washed with water
(2.times.200 ml), then dried over MgSO.sub.4 and evaporated,
affording a yellow solid which was purified by washing with cold
ether providing pure 6-bromo-3,4-dihydro-1H-quinolin-2-one (13.6 g,
60.3 mmol, 89%) as colorless needles.
Synthesis Example 2
6-Bromo-1-methyl-3,4-dihydro-1H-quinolin-2-one
[0249] To a solution of 6-bromo-3,4-dihydro-1H-quinolin-2-one (339
mg, 1.50 mmol) in 15 ml dry DMF was added potassium tert-butylate
(336 mg, 3.0 mmol). After the mixture was stirred for 30 min at
room temperature, a solution of methyl iodide (426 mg, 3.0 mmol) in
5 ml dry DMF was added. Following overnight stirring, the mixture
was diluted with 100 ml 1 N HCl. Extraction with ethyl acetate
(2.times.100 mL) followed by washing of the organic extracts with
water and brine, drying over MgSO.sub.4 and removal of the solvent
in vacuo gave a light yellow solid. Purification by flash
chromatography (hexanes/ethyl acetate, 7/3, R.sub.f=0.21) gave
6-bromo-1-methyl-3,4-dihydro-1H-quinolin-2-one (281 mg, 1.17 mmol,
78%) as colorless needles.
Synthesis Example 3
6-Bromo-1-ethyl-3,4-dihydro-1H-quinolin-2-one
[0250] To a solution of 6-bromo-3,4-dihydro-1H-quinolin-2-one (750
mg, 3.32 mmol) in 20 ml dry DMF was added potassium tert-butylate
(804 mg, 6.64 mmol). After the mixture was stirred for 30 min at
room temperature, a solution of ethyl bromide (724 mg, 6.64 mmol)
in 10 ml dry DMF was added. Following overnight stirring, the
mixture was diluted with 150 ml 1 N HCl. Extraction with ethyl
acetate (2.times.100 mL) followed by washing of the organic
extracts with water and brine, drying over MgSO.sub.4 and removal
of the solvent in vacuo gave a light yellow solid. Purification by
flash chromatography (hexanes/ethyl acetate, 1/1, R.sub.f=0.52)
gave 6-bromo-1-ethyl-3,4-dihydro-1H-quinolin-2-one (583 mg, 2.29
mmol, 59%) as a colorless solid.
Synthesis Example 4
6-Bromo-1-isopropyl-3,4-dihydro-1H-quinolin-2-one
[0251] To a solution of 6-bromo-3,4-dihydro-1H-quinolin-2-one (750
mg, 3.32 mmol) in 20 ml dry DMF was added potassium tert-butylate
(804 mg, 6.64 mmol). After the mixture was stirred for 30 min at
room temperature, a solution of isopropyl bromide (814 mg, 6.64
mmol) in 10 ml dry DMF was added and the mixture heated to
80.degree. C. After stirring for additional 48 h, the mixture was
cooled to room temperature and diluted with 150 ml 1 N HCl.
Extraction with ethyl acetate (2.times.100 mL) followed by washing
of the organic extracts with water and brine, drying over
MgSO.sub.4 and removal of the solvent in vacuo gave a light yellow
solid. Purification by flash chromatography (hexanes/ethyl acetate,
4/1, R.sub.f=0.21) gave
6-bromo-1-isopropyl-3,4-dihydro-1H-quinolin-2-one (347 mg, 1.29
mmol, 33%) as pale yellow solid.
Synthesis Example 5
1,2,5,6-Tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-one
[0252] A solution of 3-chloropropanoyl chloride (9.1 ml, 95.0 mmol)
in 20 ml dry acetone was added dropwise to a solution of indoline
(20.5 g, 0.21 mol) in 80 ml dry acetone and the mixture was
refluxed for 1 h. After cooling to ambient temperature the solution
was poured into 500 ml stirred 2N HCl and extracted with ethyl
acetate (3.times.150 ml). After washing with 1N HCl and brine and
drying over MgSO.sub.4 the solvent was removed under reduced
pressure and the crude product was obtained as a pale yellow solid.
This was added portionwise to a molten mixture of AlCl.sub.3 (60.0
g, 0.45 mol) and NaCl (17.5 g, 300 mmol) at 150.degree. C. and
stirred for additional 30 min. On cooling, excess aluminum chloride
was decomposed by the addition of a chilled mixture of 20 ml
concentrated hydrochloric acid and 500 ml water. Extraction with
ethyl acetate (3.times.200 ml), followed by drying over MgSO.sub.4
and removal of the solvent gave a yellow solid, which was purified
by crystallization from acetone/ether yielding
1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-one (11.8 g, 65.8
mmol, 69%) as colorless needles.
Synthesis Example 6
1,2,6,7-Tetrahydro-5H-pyrido[3,2,1-ij]quinolin-3-one
[0253] A solution of 3-chloropropanoyl chloride (9.1 ml, 95.0 mmol)
in 20 ml dry acetone was added dropwise to a solution of
1,2,3,4-tetrahydroquinoline (26.6 g, 0.20 mol) in 80 ml dry acetone
and the mixture was refluxed for 1 h. After cooling to ambient
temperature the solution was poured into 500 ml stirred 2N HCl and
extracted with ethyl acetate (3.times.150 ml). After washing with
1N HCl and brine and drying over MgSO.sub.4 the solvent was removed
under reduced pressure and the crude product was obtained as a pale
yellow solid. This was added portionwise to a molten mixture of
AlCl.sub.3 (60.0 g, 0.45 mol) and NaCl (17.5 g, 300 mmol) at
150.degree. C. and stirred for additional 30 minutes. On cooling,
excess aluminum chloride was decomposed by the addition of a
chilled mixture of 20 ml concentrated hydrochloric acid and 500 ml
water. Extraction with ethyl acetate (3.times.200 ml), followed by
drying over MgSO.sub.4 and removal of the solvent gave
1,2,6,7-tetrahydro-5H-pyrido[3,2,1-ij]quinolin-3-one (15.6 g, 83.3
mmol, 88%) as a yellow solid.
Synthesis Example 7
8-Bromo-1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-one
[0254] To a solution of
1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-one (10.0 g, 55.8
mmol) in 100 ml dry DMF was added dropwise a solution of
N-bromosuccinimide (10.4 g, 58.6 mmol) in 150 ml dry DMF at
0.degree. C. The mixture was stirred at 0.degree. C. for 2 h, then
400 ml water was added and the solution was extracted with ethyl
acetate (3.times.150 ml). The organic phase was washed with water
(2.times.200 mL), then dried over MgSO.sub.4 and evaporated,
affording a yellow solid, which was purified by crystallization
from acetone/ether providing pure
8-bromo-1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]-quinolin-4-one (12.8
g, 50.8 mmol, 91%) as pale yellow needles.
Synthesis Example 8
9-Bromo-1,2,6,7-tetrahydro-5H-pyrido[3,2,1-ij]quinolin-3-one
[0255] To a solution of
1,2,6,7-tetrahydro-5H-pyrido[3,2,1-ij]quinolin-3-one (9.1 g, 48.6
mmol) in 100 ml dry DMF was added dropwise a solution of
N-bromosuccinimide (9.08 g, 51.0 mmol) in 150 ml dry DMF at
0.degree. C. The mixture was stirred at 0.degree. C. for 2 h, then
400 ml water was added and the solution was extracted with ethyl
acetate (3.times.150 ml). The organic phase was washed with water
(2.times.200 ml), then dried over MgSO.sub.4 and evaporated,
affording a yellow solid, which was purified by crystallization
from acetone/ether providing pure
9-bromo-1,2,6,7-tetrahydro-5H-pyrido[3,2,1-ij]quinolin-3-one (6.53,
24.5 mmol, 50%) as pale yellow needles.
Synthesis Example 9
8-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-0)-1,2,5,6-tetrahydro-pyrrolo-
[3,2,1-ij]quinolin-4-one
[0256] To a solution of bis(pinacolato)diboron (1.75 g, 6.90 mmol),
potassium acetate (1.96 g, 20.0 mmol) and
[1,1-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (158 mg,
0.19 mmol) in 50 ml degassed DMSO was added
8-bromo-1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-one (1.58 g,
6.30 mmol) under an atmosphere of nitrogen, and the mixture was
stirred for 2 h at 80.degree. C. After cooling to ambient
temperature the solution was poured into 100 ml water and extracted
with ethyl acetate (3.times.100 ml). The combined organic layers
were washed with water (3.times.100 ml), dried over MgSO.sub.4 and
concentrated in vacuo to give the crude product which was
crystallized from acetone to yield pure
8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2,5,6-tetrahydro-pyrro-
lo[3,2,1-ij]quinolin-4-one (1.40 g, 4.68 mmol, 74%) as pale yellow
plates.
Synthesis Example 10
6-Bromo-8-fluoro-3,4,4a,8a-tetrahydro-1H-quinolin-2-one
[0257] This intermediate was obtained according to general
procedure I from 8-fluoro-3,4,4a,8a-tetrahydro-1H-quinolin-2-one
(515 mg, 3.12 mmol) and NBS (583 mg, 3.27 mmol) after flash
chromatography on silica gel (hexanes/ethyl acetate, 5/1,
R.sub.f=0.32) as white solid (647 mg, 2.65 mmol, 85%).
Synthesis Example 11
6-Bromo-7-fluoro-3,4,4a,8a-tetrahydro-1H-quinolin-2-one
[0258] This intermediate was obtained according to general
procedure I from 7-fluoro-3,4,4a,8a-tetrahydro-1H-quinolin-2-one
(92 mg, 0.56 mmol) and NBS (104 mg, 0.58 mmol) after flash
chromatography on silica gel (hexanes/ethyl acetate, 5/1,
R.sub.f=0.27) as white solid (120 mg, 0.49 mmol, 88%).
Synthesis Example 12
6-Bromo-7-hydroxy-3,4,4a,8a-tetrahydro-1H-quinolin-2-one
[0259] This intermediate was obtained according to general
procedure I from 7-hydroxy-3,4,4a,8a-tetrahydro-1H-quinolin-2-one
(370 mg, 2.27 mmol) and NBS (424 mg, 2.38 mmol) after flash
chromatography on silica gel (hexanes/ethyl acetate, 1/1,
R.sub.f=0.15) as white solid (500 mg, 2.07 mmol, 91%).
Synthesis Example 13
2-(4-Bromo-2-fluorophenylamino)-2-oxoethyl acetate
[0260] To a solution of 4-bromo-2-fluoroaniline (9.5 g, 50.0 mmol)
in 150 ml dry CHCl.sub.3 was added drop wise acetoxyacetyl chloride
(7.5 g, 55.0 mmol) under nitrogen. The mixture was stirred at room
temperature for 0.5 h, then water was added and the solution was
extracted several times with dichloromethane. The combined organic
layers were washed with brine, dried over MgSO.sub.4 and
evaporated, affording 2-(4-bromo-2-fluorophenylamino)-2-oxoethyl
acetate (15.2 g) as colorless solid in quantitative yield.
Synthesis Example 14
N-(4-Bromo-2-fluorophenyl)-2-hydroxyacetamide
[0261] To a solution of 2-(4-Bromo-2-fluorophenylamino)-2-oxoethyl
acetate (14.2 g, 49.0 mmol) in 150 ml ethanol was added a 2 M
solution of NaOH (49 ml, 97.9 mmol) at 0.degree. C. The mixture was
stirred at room temperature for 0.5 h, then water was added.
Acidification of the solution with 3 M HCl afforded after
filtration and drying overnight over silica gel
N-(4-bromo-2-fluorophenyl)-2-hydroxyacetamide (9.1 g, 36.6 mmol,
75%) as colorless solid.
Synthesis Example 15
7-Bromo-2H-benzo[b][1,4]oxazin-3(4H)-one
[0262] A solution of N-(4-bromo-2-fluorophenyl)-2-hydroxyacetamide
(8.0 g, 32.3 mmol) in 50 ml dry DMF was added drop wise to a
suspension of sodium hydride (5.2 g, 129 mmol) in 30 ml dry DMF and
the mixture was stirred for 2 h under an atmosphere of nitrogen at
140.degree. C. After cooling to ambient temperature water was added
and the mixture was extracted several times with ethyl acetate.
After washing the combined organic layers with brine and drying
over MgSO.sub.4 the solvent was removed under reduced pressure and
the crude product was obtained as a pale yellow solid. Purification
by flash chromatography on silica gel (dichloromethane/methanol,
97/3, R.sub.f=0.35) yielded
7-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one (2.3 g, 10.1 mmol, 31%) as
off-white solid.
Synthesis Example 16
N-(4-Bromo-2-nitrophenyl)-2-chloroacetamide
[0263] To a solution of 4-bromo-2-nitroaniline (15.0 g, 69.1 mmol)
was added drop wise 2-chloroacetyl chloride (9.4 g, 82.9 mmol)
under nitrogen. After refluxing for 1.5 h, the reaction mixture was
cooled to ambient temperature and the solvent was removed under
reduced pressure. Crystallization from ethyl acetate/hexane
afforded N-(4-bromo-2-nitrophenyl)-2-chloroacetamide (19.4 g, 66.1
mmol, 96%) as yellow needles.
Synthesis Example 17
N-(2-Amino-4-bromophenyl)-2-chloroacetamide
[0264] Ferrous powder (19.8 g, 354 mmol), ammonium chloride (1.1 g,
19.7 mmol) and acetic acid (4.9 ml, 86.5 mmol) were suspended in
300 ml water and stirred at 50.degree. C. for 15 min. To this
mixture, a solution of N-(4-bromo-2-nitrophenyl)-2-chloroacetamide
(11.5 g, 39.3 mmol) in 100 ml DMF was added quickly. After stirring
for 15 min, the mixture was basified to pH 9 with aqueous sodium
carbonate solution. The remaining solids were filtered and washed
with water and ethyl acetate. Extraction of the water layer with
ethyl acetate, washing of the combined organic layers with brine,
drying over MgSO.sub.4, removing the solvent under reduced pressure
and purification of the crude product by flash chromatography on
silica gel (petroleum ether/ethyl acetate, 1/1) yielded
N-(2-amino-4-bromophenyl)-2-chloroacetamide (4.5 g, 17.0 mmol, 43%)
as an off-white solid.
Synthesis Example 18
6-Bromo-3,4-dihydroquinoxalin-2(1H)-one
[0265] A mixture of N-(2-amino-4-bromophenyl)-2-chloroacetamide
(4.5 g, 17.0 mmol), sodium iodide (101 mg, 2.0 mmol) and sodium
carbonate (3.6 g, 33.8 mmol) in 300 ml acetonitrile was refluxed
overnight under an atmosphere of nitrogen. Then the acetonitrile
was removed under vacuum. The resulting solid was suspended in 150
ml water acidified to pH 5-6 with 1 N HCl. Extraction with ethyl
acetate, washing of the combined organic layers with brine, drying
over MgSO.sub.4, removing the solvent under reduced pressure and
purification of the crude product by flash chromatography on silica
gel (petroleum ether/ethyl acetate, 1.5/1) yielded
6-bromo-3,4-dihydroquinoxalin-2(1H)-one (1.3 g, 5.8 mmol, 34%) as
yellow solid.
Synthesis Example 19
6-Bromo-4-methyl-3,4-dihydroquinoxalin-2(1H)-one
[0266] To a solution of 6-bromo-3,4-dihydroquinoxalin-2(1H)-one
(370 mg, 1.63 mmol) in 10 ml methanol was added a solution of 37%
formaldehyde in water (59 mg, 1.95 mmol) and acetic acid (196 mg,
3.26 mmol). The mixture was stirred at room temperature for 2 h,
then refluxed for 1 h. After addition of NaBH.sub.3CN (307 mg, 4.89
mmol) stirring was continued for 2.5 h at room temperature. Then
methanol was removed under vacuum. To the remaining mixture water
was added. Then the solution was basified to pH 8-9 with an aqueous
solution of sodium hydrogen carbonate and extracted several times
with ethyl acetate. The combined organic layers were washed with
brine, dried over MgSO.sub.4 and evaporated, affording
6-bromo-4-methyl-3,4-dihydroquinoxalin-2(1H)-one (369 mg, 1.53
mmol, 94%) as off-white solid.
Synthesis Example 20
(2-Amino-5-bromophenyl)methanol
[0267] To a suspension of lithium aluminium hydride (0.33 g, 8.7
mmol) in THF (10 ml) was added a solution of methyl
2-amino-5-bromobenzoate (2.0 g, 8.7 mmol) in 20 ml THF at 0.degree.
C. under nitrogen. Then stirring was continued for 2 h. 0.64 ml
water, 2 M solution of sodium hydroxide (0.64 ml) and again 1.28 ml
water were added before the resulting mixture was filtered through
celite. Evaporation of the solvent and purification of the crude
product by flash chromatography on silica gel
(dichloromethane/ethyl acetate, 2/1) yielded
(2-amino-5-bromophenyl)methanol (1.0 g, 5.2 mmol, 59%) as off-white
solid.
Synthesis Example 21
6-Bromo-1H-benzo[d][1,3]oxazin-2(4H)-one
[0268] To a solution of (2-amino-5-bromophenyl)methanol (772 mg,
3.8 mmol) in 15 ml THF was added triphosgene (1.03 g, 3.8 mmol)
under nitrogen. After precipitation of a colorless solid, stirring
was continued for 20 min before water was added. The solution was
extracted several times with ethyl acetate. The combined organic
layers were washed with brine, dried over MgSO.sub.4 and
evaporated, affording 6-bromo-1H-benzo[d][1,3]oxazin-2(4H)-one (830
mg, 3.64 mmol, 96%) as colorless solid.
Synthesis Example 22
8-(Tributylstannyl)-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-4-one
[0269] To a solution of
8-bromo-1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-one (9.07 g,
36.0 mmol) and 1,1,1,2,2,2-hexabutyldistannane (29.1 mL, 57.6 mmol)
in 40 mL degassed dry toluene was added
tetrakis(triphenylphosphine)palladium(0) (4.16 g, 3.60 mmol) under
an atmosphere of nitrogen, and the mixture was stirred overnight at
90.degree. C. After cooling to ambient temperature the mixture was
concentrated in vacuo. The crude product was purified by flash
chromatography on silica gel (hexanes/ethyl acetate, 1/10,
R.sub.f=0.1) to yield pure
8-(tributylstannyl)-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-4-one
as a light yellow oil (7.50 g, 16.2 mmol, 45%).
Synthesis Example 23
8-Acetyl-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-4-one
[0270] To a suspension of
1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-one (700 mg, 4.04
mmol) and AlCl.sub.3 (3.61 g, 27.0 mmol) in CS.sub.2 (20 mL) was
added dropwise acetyl chloride (0.34 mL, 6.06 mmol) at 0.degree. C.
The mixture was warmed to ambient temperature and refluxed for 18 h
before being cooled down to 0.degree. C. A mixture of ice/water was
added to quench and a precipitate was formed and filtered to yield
a pale yellow solid (802 mg, 3.73 mmol, 92%) which was sufficiently
pure for further use.
General Experimental Procedures for the Synthesis of the Compounds
of the Examples
[0271] General procedure A: Microwave enhanced Suzuki coupling.
Pyridine boronic acid (0.75 mol, 1 equivalent), aryl bromide
(0.9-1.3 equivalents), and
tetrakis(triphenyl-phosphane)palladium(0) (43 mg, 37.5 .mu.mol, 5
mol %) were suspended in 1.5 ml DMF in a 10 mL septum-capped tube
containing a tiny stirring magnet. To this was added a solution of
NaHCO.sub.3 (189 mg, 2.25 mmol, 3 equivalents) in 1.5 ml water and
the vial was sealed tightly with an Teflon crimp top. The mixture
was irradiated for 15 min at a temperature of 150.degree. C. with
an initial irradiation power of 100 W. After the reaction, the vial
was cooled to 40.degree. C. by gas jet cooling, the crude mixture
was partitioned between ethyl acetate and water and the aqueous
layer was extracted three times with ethyl acetate. The combined
organic layers were dried over MgSO.sub.4 and the solvents were
removed in vacuo. The coupling products were obtained after flash
chromatography on silica gel and/or crystallization. If an oil was
obtained, it was transferred into the hydrochloride salt by
addition of 1N HCl solution in diethylether and/or THF.
[0272] General procedure B: Suzuki coupling with conventional
heating. Pyridine boronic acid (1 equivalent), aryl bromide
(1.3-1.5 equivalents), and
tetrakis(triphenyl-phosphane)palladium(0) (5 mol %) were suspended
in toluene/ethanol 4/1 to give a 0.07-0.1 M solution of boronic
acid under an atmosphere of nitrogen. To this was added a 1 N
aqueous solution of Na.sub.2CO.sub.3 (6 equivalents). The mixture
was then refluxed for 12-18 h, cooled to room temperature, diluted
with water and extracted several times with ethyl acetate. The
combined extracts were dried over MgSO.sub.4, concentrated and
purified by flash chromatography on silica gel and/or
crystallization. If an oil was obtained, it was transferred into
the hydrochloride salt by addition of 1N HCl solution in
diethylether and/or THF.
[0273] General procedure C: Suzuki coupling reaction. To a
suspension of aryl bromide (1 equivalent), boronic acid (1.2-1.3
equivalents), Na.sub.2CO.sub.3 (5-6 equivalents) in DME/water (3/1)
was added tetrakis(triphenylphosphane)palladium(0) (5 mol %) under
an atmosphere of nitrogen. The reaction mixture was then refluxed
for 3.5-16 h. After being cooled to room temperature, it was
diluted with water and extracted several times with ethyl acetate.
The combined extracts were washed with brine, dried over
MgSO.sub.4, concentrated and purified by flash chromatography on
silica gel and if necessary crystallization.
[0274] General procedure D: Sulfuration. To a suspension of the
corresponding quinolinone (1 equivalent) in dry toluene (50 mL) was
added Lawesson's reagent (0.6 equivalents). Then the reaction
mixture was heated to reflux over night under N.sub.2. After being
cooled to room temperature, it was diluted with water and extracted
several times with ethyl acetate. The combined extracts were washed
with brine, dried over MgSO.sub.4, concentrated and purified by
flash chromatography on silica gel and/or crystallization.
[0275] General procedure E: Imidazolization.
8-(Tributylstannyl)-1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-one
(1.0 equivalent), dichlorobis(triphenylphosphine)palladium(II) (0.1
equivalents) and an acyl chloride (2.0 equivalents) were suspended
in dry toluene under an atmosphere of nitrogen. The mixture was
refluxed for 2 h before it was concentrated in vacuo. The resulting
residue was purified by flash chromatography on silica gel
(hexanes/ethyl acetate) to yield a ketone. This ketone (1.0
equivalent) was dissolved in methanol and sodium boron hydride (1.0
equivalent) was added in several portions at 0.degree. C. After
stirring for 1 h, water was added and the mixture was extracted
with ethyl acetate. Drying of the combined organic layers over
MgSO.sub.4 and removal of the solvent gave the alcohol as crude
product. The obtained alcohol was added to a solution of
thionylbis(imidazole) (4.0 equivalents) in THF at 0.degree. C.
After being stirred at ambient temperature for 15-40 h, it was
concentrated in vacuo and diluted with water followed by extraction
with dichloromethane three times. The combined extracts were washed
with brine, dried over MgSO.sub.4 and concentrated in vacuo. The
product was obtained after flash chromatography on silica gel
(methanol/dichloromethane).
Example 1
6-Pyridin-3-yl-3,4-dihydro-1H-quinolin-2-one
##STR00036##
[0277] The title compound was obtained via Suzuki coupling
according to general procedure B from
6-bromo-3,4-dihydro-1H-quinolin-2-one (2.71 g, 12.0 mmol) and
3-pyridineboronic acid (1.23 g, 10.0 mmol) after crystallization
from acetone/diethylether as colorless needles (2.15 g, 9.59 mmol,
96%), mp (acetone/diethylether) 189.degree. C. .sup.1H-NMR (500
MHz, DMSO-d.sub.6): .delta.=2.49 (t, .sup.3J=7.3 Hz, 2H), 2.95 (t,
.sup.3J=7.3 Hz, 2H), 6.95 (d, .sup.3J=8.2 Hz, 1H), 7.43 (ddd,
.sup.3J=7.9 Hz, .sup.3J=4.7 Hz, .sup.5J=0.6 Hz, 1H), 7.51 (dd,
.sup.3J=8.2 Hz, .sup.4J=2.2 Hz, 1H), 7.56 (d, .sup.4J=2.1 Hz, 1H),
8.00 (ddd, .sup.3J=7.9 Hz, .sup.4J=2.2 Hz, .sup.4J=1.6 Hz, 1H),
8.50 (dd, .sup.3J=4.7 Hz, .sup.4J=1.5 Hz, 1H), 8.84 (d, .sup.4J=2.2
Hz, 1H), 10.19 (s, 1H). .sup.13C-NMR (125 MHz, DMSO-d.sub.6):
.delta.=24.8, 30.3, 115.6, 123.8, 124.3, 125.6, 126.2, 130.6,
133.4, 135.2, 138.4, 147.2, 147.8, 170.2. MS m/z 225.25
(MH.sup.+).
[0278] According to Example 1 using the general experimental
procedures A or B and the suitable starting compounds (see Schemes
1-19) the following compounds are synthesized:
##STR00037## ##STR00038## ##STR00039## ##STR00040## ##STR00041##
##STR00042## ##STR00043## ##STR00044##
Example 2
1-Methyl-6-pyridin-3-yl-3,4-dihydro-1H-quinolin-2-one
##STR00045##
[0280] The title compound was obtained via Suzuki coupling
according to general procedure A from
6-bromo-1-methyl-3,4-dihydro-1H-quinolin-2-one (110 mg, 0.46 mmol)
and 3-pyridineboronic acid (74 mg, 0.6 mmol) after flash
chromatography on silica gel (hexanes/ethyl acetate, 2/3,
R.sub.f=0.07) as colorless needles (83 mg, 0.35 mmol, 75%), mp
(hexanes/ethyl acetate) 101.degree. C. .sup.1H-NMR (500 MHz,
CDCl.sub.3): .delta.=2.68 (t, .sup.3J=7.3 Hz, 2H), 2.97 (t,
.sup.3J=7.3 Hz, 2H), 3.38 (s, 3H), 7.06 (d, .sup.3J=8.2 Hz, 1H),
7.33 (ddd, .sup.3J=7.9 Hz, .sup.3J=4.8 Hz, .sup.5J=0.6 Hz, 1H),
7.37 (d, .sup.4J=2.1 Hz, 1H), 7.45 (dd, .sup.3J=8.3 Hz, .sup.4J=2.2
Hz, 1H), 7.82 (ddd, .sup.3J=7.9 Hz, .sup.4J=2.2 Hz, .sup.4J=1.6 Hz,
1H), 8.55 (dd, .sup.3J=4.7 Hz, .sup.4J=1.6 Hz, 1H), 8.81 (d,
.sup.4J=2.2 Hz, 1H). .sup.13C-NMR (125 MHz, CDCl.sub.3):
.delta.=25.5, 29.6, 31.6, 115.2, 123.5, 126.0, 126.3, 126.9, 132.2,
133.9, 135.7, 140.6, 147.9, 148.3, 170.2. MS m/z 239.80.
Example 3
5-Pyridin-3-yl-1,3-dihydro-indol-2-one
##STR00046##
[0282] The title compound was obtained via Suzuki coupling
according to general procedure A from
5-Bromo-1,3-dihydro-indol-2-one (159 mg, 0.75 mmol) and
3-pyridineboronic acid (123 mg, 1.0 mmol) after crystallization
from acetone/diethylether as pale yellow needles (129 mg, 0.61
mmol, 77%), mp (acetone/diethylether) 220.degree. C. .sup.1H-NMR
(500 MHz, DMSO-d.sub.6): .delta.=3.53 (s, 2H), 6.91 (d, .sup.3J=7.9
Hz, 1H), 7.42 (dd, .sup.3J=7.9 Hz, .sup.3J=4.7 Hz, 1H), 7.52 (d,
.sup.3J=7.9 Hz, 1H), 7.56 (s, 1H), 7.97 (m, 1H), 8.49 (dd,
.sup.3J=4.7 Hz, .sup.4J=1.3 Hz, 1H), 8.81 (d, .sup.4J=2.2 Hz, 1H),
10.50 (s, 1H). .sup.13C-NMR (125 MHz, DMSO-d.sub.6): .delta.=35.8,
109.6, 123.0, 123.8, 126.3, 126.9, 130.2, 133.5, 135.8, 143.9,
147.2, 147.7, 176.3. MS m/z 211.01 (MH.sup.+).
[0283] According to Example 3 using the general experimental
procedures A or B and the suitable starting compounds the following
compounds are synthesized:
##STR00047## ##STR00048## ##STR00049## ##STR00050## ##STR00051##
##STR00052## ##STR00053##
Example 4
6-(5-Methoxypyridin-3-yl)-3,4-dihydro-1H-quinolin-2-one
##STR00054##
[0285] The title compound was obtained via Suzuki coupling
according to general procedure A from
6-bromo-3,4-dihydro-1H-quinolin-2-one (170 mg, 0.75 mmol) and
5-methoxy-3-pyridineboronic acid (150 mg, 0.98 mmol) after
crystallization from acetone/diethylether as colorless needles (77
mg, 0.30 mmol, 40%), mp (acetone/diethylether) 215.degree. C.
.sup.1H-NMR (500 MHz, DMSO-d.sub.6): .delta.=2.50 (t, .sup.3J=7.6
Hz, 2H), 2.96 (t, .sup.3J=7.9 Hz, 2H), 3.89 (s, 3H), 6.95 (d,
.sup.3J=8.2 Hz, 1H), 7.53 (dd, .sup.3J=8.2 Hz, .sup.4J=1.9 Hz, 1H),
7.55 (dd, .sup.4J=2.8 Hz, .sup.4J=1.9 Hz, 1H), 7.59 (d, .sup.4J=1.6
Hz, 1H), 8.22 (d, .sup.4J=2.5 Hz, 1H), 8.44 (d, .sup.4J=1.6 Hz,
1H), 10.20 (s, 1H). .sup.13C-NMR (125 MHz, DMSO-d.sub.6):
.delta.=24.8, 30.3, 55.6, 115.5, 117.7, 124.3, 125.8, 126.4, 130.4,
135.8, 136.1, 138.5, 139.4, 155.6, 170.2. MS m/z 255.02
(MH.sup.+).
Example 5
6-Isoquinolin-4-yl-3,4-dihydro-1H-quinolin-2-one
##STR00055##
[0287] The title compound was obtained via Suzuki coupling
according to general procedure A from
6-bromo-3,4-dihydro-1H-quinolin-2-one (170 mg, 0.75 mmol) and
4-isoquinolineboronic acid (170 mg, 0.98 mmol) after
crystallization from acetone/diethylether as colorless needles (109
mg, 0.40 mmol, 53%), mp (acetone/diethylether) 222.degree. C.
.sup.1H-NMR (500 MHz, DMSO-d.sub.6): .delta.=2.51 (t, .sup.3J=7.3
Hz, 2H), 2.96 (t, .sup.3J=7.3 Hz, 2H), 7.02 (d, .sup.3J=8.2 Hz,
1H), 7.29 (dd, .sup.4J=8.2 Hz, .sup.4J=1.9, 1H), 7.34 (s, 1H) 7.70
(m, 1H), 7.76 (m, 1H) 7.88 (d, .sup.3J=8.2 Hz, 1H), 8.17 (d,
.sup.3J=7.9 Hz, 1H), 8.39 (s, 1H), 9.29 (s, 1H), 10.26 (s, 1H).
.sup.13C-NMR (125 MHz, DMSO-d.sub.6): .delta.=24.8, 30.3, 115.2,
124.0, 124.2, 127.4, 128.0, 128.7, 129.2, 129.9, 130.9, 132.2,
133.3, 138.2, 142.3, 151.6, 170.3. MS m/z 275.04 (MH.sup.+).
Example 6
6-(5-Methoxypyridin-3-yl)-1-methyl-3,4-dihydro-1H-quinolin-2-one
##STR00056##
[0289] The title compound was obtained via Suzuki coupling
according to general procedure A from
6-bromo-1-methyl-3,4-dihydro-1H-quinolin-2-one (200 mg, 0.83 mmol)
and 5-methoxy-3-pyridineboronic acid (115 g, 0.75 mmol) after
crystallization from acetone/diethylether as colorless needles (132
mg, 0.50 mmol, 66%), mp (acetone/diethylether) 159.degree. C.
.sup.1H-NMR (500 MHz, CDCl.sub.3): .delta.=2.69 (t, .sup.3J=7.9 Hz,
2H), 2.98 (t, .sup.3J=7.9 Hz, 2H), 3.39 (s, 3H), 3.91 (s, 3H), 7.06
(d, .sup.3J=8.2 Hz, 1H), 7.33 (dd, .sup.4J=2.8 Hz, .sup.4J=1.9 Hz,
1H), 7.37 (d, .sup.4J=2.2 Hz, 1H), 7.46 (dd, .sup.3J=8.5 Hz,
.sup.4J=2.2 Hz, 1H), 8.27 (d, .sup.4J=2.8 Hz, 1H), 8.43 (d,
.sup.4J=1.9 Hz, 1H). .sup.13C-NMR (125 MHz, CDCl.sub.3):
.delta.=25.5, 29.6, 31.6, 55.7, 115.2, 118.7, 126.2, 126.5, 126.9,
132.1, 135.8, 136.5, 140.4, 140.7, 155.8, 170.3. MS m/z 268.95
(MH.sup.+).
Example 7
6-Isoquinolin-4-yl-1-methyl-3,4-dihydro-1H-quinolin-2-one
##STR00057##
[0291] The title compound was obtained via Suzuki coupling
according to general procedure A from
6-bromo-1-methyl-3,4-dihydro-1H-quinolin-2-one (264 mg, 1.10 mmol)
and 4-isoquinolineboronic acid (172 mg, 1.0 mmol) after
crystallization from acetone/diethylether as colorless needles (163
mg, 0.57 mmol, 57%), mp (acetone/diethylether) 176.degree. C.
.sup.1H-NMR (500 MHz, CDCl.sub.3): .delta.=2.73 (t, .sup.3J=7.6 Hz,
2H), 2.99 (t, .sup.3J=7.7 Hz, 2H), 3.43 (s, 3H), 7.12 (d,
.sup.3J=8.2 Hz, 1H), 7.32 (d, .sup.4J=1.9, 1H), 7.40 (dd,
.sup.3J=8.2 Hz, .sup.4J=2.2 Hz, 1H), 7.63 (m, 1H), 7.68 (m, 1H),
7.91 (d, .sup.3J=7.9 Hz, 1H), 8.03 (d, .sup.3J=7.6 Hz, 1H), 8.46
(s, 1H), 9.24 (s, 1H). .sup.13C-NMR (125 MHz, CDCl.sub.3):
.delta.=25.4, 29.6, 31.6, 114.8, 124.6, 126.5, 127.2, 128.0, 128.4,
129.1, 129.3, 130.6, 131.5, 132.4, 134.2, 140.4, 142.8, 152.0,
170.4. MS m/z 289.91 (MH.sup.+).
Example 8
6-Pyridin-3-yl-3,4-dihydro-1H-quinoline-2-thione
##STR00058##
[0293] A mixture of 6-Pyridin-3-yl-3,4-dihydro-1H-quinolin-2-one
(395 mg, 1.76 mmol) and Lawessons reagent (356 mg, 0.88 mmol) was
refluxed in 30 ml toluene for 2 h. After evaporation of the solvent
under reduced pressure, the residue was purified by flash
chromatography on silica gel (hexanes/ethyl acetate, 3/7,
R.sub.f=0.31) which gave
6-Pyridin-3-yl-3,4-dihydro-1H-quinoline-2-thione as yellow plates
(63 mg, 0.26 mmol, 15%), mp (hexanes/ethyl acetate) 267.degree. C.
.sup.1H-NMR (500 MHz, DMSO-d.sub.6): .delta.=2.87 (m, 2H), 2.97 (m,
2H), 7.20 (d, .sup.3J=8.2 Hz, 1H), 7.46 (dd, .sup.3J=7.9 Hz,
.sup.3J=4.6 Hz, 1H), 7.59 (dd, .sup.3J=8.2 Hz, .sup.4J=1.9 Hz, 1H),
7.62 (d, .sup.4J=1.9 Hz, 1H), 8.04 (m, 1H), 8.53 (dd, .sup.3J=4.7
Hz, .sup.4J=1.6 Hz, 1H), 8.87 (d, .sup.4J=2.2 Hz, 1H), 12.30 (s,
1H). MS m/z=241.05 (MH.sup.+).
[0294] According to Example 8 using the suitable substituted
6-pyridin-3-yl-3,4-dihydro-1H-quinolin-2-one derivatives (see
Schemes 1-19) the following compounds are synthesized:
##STR00059## ##STR00060##
Example 9
1-Ethyl-6-pyridin-3-yl-3,4-dihydro-1H-quinolin-2-one
##STR00061##
[0296] The title compound was obtained via Suzuki coupling
according to general procedure A from
6-bromo-1-ethyl-3,4-dihydro-1H-quinolin-2-one (229 mg, 0.9 mmol)
and 3-pyridineboronic acid (92 mg, 0.75 mmol) after flash
chromatography on silica gel (hexanes/ethyl acetate, 1/1,
R.sub.f=0.09) and crystallization from acetone/diethylether as
colorless plates (125 mg, 0.50 mmol, 66%), mp
(acetone/diethylether) 91.degree. C. .sup.1H-NMR (500 MHz,
CDCl.sub.3): .delta.=1.30 (t, .sup.3J=7.3 Hz, 3H), 2.70 (t,
.sup.3J=7.6 Hz, 2H), 2.99 (t, .sup.3J=7.6 Hz, 2H), 4.04 (q,
.sup.3J=7.3 Hz, 2H), 7.13 (d, .sup.3J=8.2 Hz, 1H), 7.37 (ddd,
.sup.3J=7.9 Hz, .sup.3J=4.7 Hz, .sup.5J=0.6 Hz, 1H), 7.41 (d,
.sup.4J=2.2 Hz, 1H), 7.48 (dd, .sup.3J=8.5 Hz, .sup.4J=2.2 Hz, 1H),
7.85 (ddd, .sup.3J=7.9 Hz, .sup.4J=2.2 Hz, .sup.4J=1.6 Hz, 1H),
8.58 (dd, .sup.3J=5.0 Hz, .sup.4J=1.6 Hz, 1H), 8.84 (dd,
.sup.4J=2.5 Hz, .sup.5J=0.6 Hz, 1H). .sup.13C-NMR (125 MHz,
CDCl.sub.3): .delta.=12.8, 25.7, 31.8, 37.4, 115.2, 123.6, 126.1,
126.7, 127.3, 132.2, 133.9, 135.7, 139.6, 148.0, 148.4, 169.7. MS
m/z 253.00 (MH.sup.+).
Example 10
1-Isopropyl-6-pyridin-3-yl-3,4-dihydro-1H-quinolin-2-one
##STR00062##
[0298] The title compound was obtained via Suzuki coupling
according to general procedure A from
6-bromo-1-isopropyl-3,4-dihydro-1H-quinolin-2-one (174 mg, 0.65
mmol) and 3-pyridineboronic acid (74 mg, 0.6 mmol) after flash
chromatography on silica gel (hexanes/ethyl acetate, 1/1,
R.sub.f=0.14) as a colorless solid (74 mg, 0.18 mmol, 29%), nip
(hexanes/ethyl acetate) 101.degree. C. .sup.1H-NMR (500 MHz,
CDCl.sub.3): .delta.=1.54 (d, .sup.3J=6.9 Hz, 6H), 2.61 (t,
.sup.3J=7.3 Hz, 2H), 2.80 (t, .sup.3J=7.3 Hz, 2H), 4.73 (sep,
.sup.3J=6.9 Hz, 1H), 7.23 (d, .sup.3J=8.5 Hz, 1H), 7.35 (ddd,
.sup.3J=7.9 Hz, .sup.3J=5.0 Hz, .sup.5J=0.9 Hz, 1H), 7.38 (d,
.sup.4J=2.2 Hz, 1H), 7.43 (dd, .sup.3J=8.5 Hz, .sup.4J=2.2 Hz, 1H),
7.83 (ddd, .sup.3J=7.9 Hz, .sup.4J=2.5 Hz, .sup.4J=1.9 Hz, 1H),
8.56 (dd, .sup.3J=4.7 Hz, .sup.4J=1.9 Hz, 1H), 8.84 (dd,
.sup.4J=2.2 Hz, .sup.5J=0.6 Hz, 1H). .sup.13C-NMR (125 MHz,
CDCl.sub.3): .delta.=20.2, 26.0, 33.4, 48.5, 117.0, 123.6, 125.7,
126.4, 129.2, 132.3, 133.9, 135.8, 140.4, 148.0, 148.4, 171.1. MS
m/z 267.10 (MH.sup.+).
Example 11
8-Pyridin-3-yl-1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinoline-4-one
##STR00063##
[0300] The title compound was obtained via Suzuki coupling
according to general procedure A from
8-bromo-1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-one (185 mg,
0.73 mmol) and 3-pyridineboronic acid (82 mg, 0.67 mmol) after
crystallization from acetone/diethylether as a colorless solid (83
mg, 0.33 mmol, 49%), mp (acetone/diethylether) 152.degree. C.
.sup.1H-NMR (500 MHz, CDCl.sub.3): .delta.=2.72 (t, .sup.3J=7.8 Hz,
2H), 3.03 (t, .sup.3J=7.8 Hz, 2H), 3.25 (t, .sup.3J=8.5 Hz, 2H),
4.13 (t, .sup.3J=8.5 Hz, 2H), 7.20 (s, 1H), 7.28 (s, 1H), 7.32
(ddd, .sup.3J=7.8 Hz, .sup.3J=4.8 Hz, .sup.5J=0.5 Hz, 1H), 7.79
(ddd, .sup.3J=7.8 Hz, .sup.4J=2.2 Hz, .sup.4J=1.6 Hz, 1H), 8.54
(dd, .sup.3J=4.7 Hz, .sup.4J=1.4 Hz, 1H), 8.59 (d, .sup.4J=2.0 Hz,
1H). .sup.13C-NMR (125 MHz, CDCl.sub.3): .delta.=24.5, 27.7, 31.6,
45.5, 120.7, 122.4, 123.5, 124.7, 129.9, 133.5, 134.0, 136.7,
141.6, 148.1, 167.6. MS m/z 251.00 (MH.sup.+).
[0301] According to Example 11 using the general experimental
procedures A or B and the suitable starting compounds (see Schemes
1-19) the following compounds are synthesized:
##STR00064## ##STR00065## ##STR00066## ##STR00067## ##STR00068##
##STR00069## ##STR00070##
Example 12
8-Chloro-6-pyridin-3-yl-3,4-dihydro-1H-quinolin-2-one
##STR00071##
[0303] To a solution of
6-Pyridin-3-yl-3,4-dihydro-1H-quinolin-2-one (560 mg, 2.50 mmol) in
5 ml dry DMF was added N-chlorosuccinimide (368 mg, 2.75 mmol) in 5
ml dry DMF over a period 2 h at 65.degree. C. After additional 3 h
at 65.degree. C., the mixture was poured into 75 ml ice water and
extracted with ethyl acetate (3.times.50 ml). The combined organic
layers were washed with water and brine, dried over MgSO.sub.4 and
the solvent was evaporated in vacuo.
8-Chloro-6-pyridin-3-yl-3,4-dihydro-1H-quinolin-2-one was obtained
after flash chromatography on silica gel (hexanes/ethyl acetate,
3/7, R.sub.f=0.15) and crystallization from acetone/diethylether as
colorless needles (225 mg, 0.87 mmol, 35%), mp
(acetone/diethylether) 178.degree. C. .sup.1H-NMR (500 MHz,
DMSO-d.sub.6): .delta.=2.54 (m, 2H), 3.01 (m, 2H), 7.45 (ddd,
.sup.3J=8.0 Hz, .sup.3J=4.8 Hz, .sup.5J=0.8 Hz, 1H), 7.60 (d,
.sup.4J=2.0 Hz, 1H), 7.69 (d, .sup.4J=2.0 Hz, 1H), 8.06 (ddd,
.sup.3J=8.0 Hz, .sup.4J=2.5 Hz, .sup.4J=1.5 Hz, 1H), 8.53 (dd,
.sup.3J=4.8 Hz, .sup.4J=1.5 Hz, 1H), 8.88 (dd, .sup.4J=2.5 Hz,
.sup.5J=0.8 Hz, 1H), 9.64 (s, 1H). .sup.13C-NMR (125 MHz,
DMSO-d.sub.6): .delta.=25.3, 30.3, 119.7, 123.8, 125.0, 125.6,
127.4, 131.7, 133.7, 133.8, 134.8, 147.3, 152.4, 170.3. MS m/z
258.95 (M.sup.+).
Example 13
8-Nitro-6-pyridin-3-yl-3,4-dihydro-1H-quinolin-2-one
##STR00072##
[0305] The title compound was obtained via Suzuki coupling
according to general procedure B from
6-bromo-8-nitro-3,4-dihydro-1H-quinolin-2-one (1.0 g, 3.70 mmol)
(prepared previously by nitration of
6-bromo-3,4-dihydro-1H-quinolin-2-one with concentrated
HNO.sub.3/H.sub.2SO.sub.4) and 3-pyridineboronic acid (546 mg, 4.44
mmol) after flash chromatography on silica gel (ethyl acetate,
R.sub.f=0.15) as yellow needles (311 mg, 1.16 mmol, 31%), mp (ethyl
acetate) 189.degree. C. .sup.1H-NMR (500 MHz, DMSO-d.sub.6):
.delta.=2.64 (t, .sup.3J=7.9 Hz, 2H), 3.13 (t, .sup.3J=7.9 Hz, 2H),
7.50 (ddd, .sup.3J=8.2 Hz, .sup.3J=4.9 Hz, .sup.5J=0.9 Hz, 1H),
8.09 (d, .sup.4J=2.1 Hz, 1H), 8.15 (ddd, .sup.3J=7.9 Hz,
.sup.4J=2.4 Hz, .sup.4J=1.5 Hz, 1H), 8.29 (d, .sup.4J=2.1 Hz, 1H),
8.59 (dd, .sup.3J=4.9 Hz, .sup.4J=1.8 Hz, 1H), 8.95 (dd,
.sup.4J=2.4 Hz, .sup.5J=0.8 Hz, 1H), 9.88 (s, 1H). .sup.13C-NMR
(125 MHz, DMSO-d.sub.6): .delta.=25.0, 29.3, 121.4, 123.9, 128.5,
130.6, 132.3, 133.1, 133.2, 134.0, 135.0, 147.4, 149.0, 170.0. MS
m/z 269.94 (MH.sup.+).
[0306] According to Example 13 using the general experimental
procedures A or B and the suitable starting compounds (see Schemes
1-19) the following compounds are synthesized:
##STR00073## ##STR00074## ##STR00075## ##STR00076##
Example 14
7-Pyridin-3-yl-4H-benzo[1,4]thiazin-3-one
##STR00077##
[0308] The title compound was obtained via Suzuki coupling
according to general procedure B from
7-Bromo-4H-benzo[1,4]thiazin-3-one (1.15 g, 4.71 mmol) and
3-pyridineboronic acid (695 mg, 5.56 mmol) after flash
chromatography on silica gel (hexanes/ethyl acetate, 1/1,
R.sub.f=0.20) and crystallization from ethanol as colorless needles
(486 mg, 2.01 mmol, 43%), mp (ethanol) 240.degree. C. .sup.1H-NMR
(500 MHz, DMSO-d.sub.6): .delta.=3.51 (s, 2H), 7.07 (d, .sup.3J=8.5
Hz, 1H), 7.44 (ddd, .sup.3J=7.9 Hz, .sup.3J=4.9 Hz, .sup.5J=0.6 Hz,
1H), 7.54 (dd, .sup.3J=8.2 Hz, .sup.4J=2.1 Hz, 1H), 7.70 (d,
.sup.4J=2.1 Hz, 1H), 8.03 (ddd, .sup.3J=7.9 Hz, .sup.4J=2.4 Hz,
.sup.4J=1.5 Hz, 1H), 8.52 (dd, .sup.3J=4.9 Hz, .sup.4J=1.5 Hz, 1H),
8.86 (dd, .sup.4J=2.4 Hz, .sup.5J=0.6 Hz, 1H), 10.68 (s, 1H). MS
m/z 242.99 (MH.sup.+).
[0309] According to Example 14 using the general experimental
procedures A or B and the suitable starting compounds (see Schemes
1-19) the following compounds are synthesized:
##STR00078## ##STR00079## ##STR00080## ##STR00081## ##STR00082##
##STR00083## ##STR00084## ##STR00085## ##STR00086## ##STR00087##
##STR00088## ##STR00089## ##STR00090## ##STR00091##
##STR00092##
Example 15
8-Chloro-6-pyridin-3-yl-3,4-dihydro-1H-quinoline-2-thione
##STR00093##
[0311] A mixture of
8-chloro-6-pyridin-3-yl-3,4-dihydro-1H-quinolin-2-one (900 mg, 3.48
mmol) and Lawessons reagent (985 mg, 2.44 mmol) was refluxed in 50
ml toluene for 2 h. After evaporation of the solvent under reduced
pressure, the residue was purified by flash chromatography on
silica gel (ethyl acetate, R.sub.f=0.26) and crystallization from
acetone/diethylether.
8-Chloro-6-pyridin-3-yl-3,4-dihydro-1H-quinoline-2-thione was
obtained as yellow needles (212 mg, 0.77 mmol, 22%), mp
(acetone/diethylether) 175.degree. C. .sup.1H-NMR (500 MHz,
DMSO-d.sub.6): .delta.=2.91 (m, 2H), 3.00 (m, 2H), 7.46 (ddd,
.sup.3J=7.9 Hz, .sup.3J=4.9 Hz, .sup.5J=0.9 Hz, 1H), 7.66 (d,
.sup.4J=2.1 Hz, 1H), 7.76 (d, .sup.4J=2.0 Hz, 1H), 8.09 (ddd,
.sup.3J=7.9 Hz, .sup.4J=2.4 Hz, .sup.4J=1.5 Hz, 1H), 8.56 (dd,
.sup.3J=4.9 Hz, .sup.4J=1.5 Hz, 1H), 8.91 (dd, .sup.4J=2.4 Hz,
.sup.5J=0.9 Hz, 1H), 11.31 (bs, 1H). .sup.13C-NMR (125 MHz,
DMSO-d.sub.5): .delta.=25.6, 39.4, 120.5, 123.8, 125.2, 126.0,
129.7, 133.4, 133.6, 133.8, 133.9, 147.5, 148.8, 201.5. MS
m/z=273.95 (M.sup.35Cl.sup.+), 275.95 (M.sup.37Cl.sup.+).
Example 16
9-Pyridin-3-yl-1,2,6,7-tetrahydro-5H-pyrido[3,2,1-ij]quinolin-3-one
##STR00094##
[0313] The title compound was obtained via Suzuki coupling
according to general procedure A from
9-bromo-1,2,6,7-tetrahydro-5H-pyrido[3,2,1-ij]quinolin-3-one (266
mg, 1.0 mmol) and 3-pyridineboronic acid (92 mg, 0.75 mmol) after
flash chromatography on silica gel (hexanes/ethyl acetate, 2/3,
R.sub.f=0.12) and crystallization from acetone/diethylether as
colorless needles (116 mg, 0.44 mmol, 59%), mp
(acetone/diethylether) 123.degree. C. .sup.1H-NMR (500 MHz,
CDCl.sub.3): .delta.=1.97 (m, 2H), 2.69 (t, .sup.3J=7.2 Hz, 2H),
2.86 (t, .sup.3J=6.3 Hz, 2H), 2.95 (t, .sup.3J=7.2 Hz, 2H), 3.90
(t, .sup.3J=6.1 Hz, 2H), 7.20-7.24 (m, 2H), 7.33 (ddd, .sup.3J=7.9
Hz, .sup.3J=4.7 Hz, .sup.5J=0.6 Hz, 1H), 7.81 (ddd, .sup.3J=7.9 Hz,
.sup.4J=2.3 Hz, .sup.4J=1.5 Hz, 1H), 8.55 (dd, .sup.3J=4.8 Hz,
.sup.4J=1.5 Hz, 1H), 8.80 (m, 1H). .sup.13C-NMR (125 MHz,
CDCl.sub.3): .delta.=21.4, 25.4, 27.4, 31.4, 41.0, 123.5, 124.4,
125.9, 126.2, 126.4, 131.9, 133.8, 135.9, 136.2, 148.0, 148.2,
169.4. MS m/z 265.18 (MH.sup.+).
Example 17
8-(5-Methoxypyridin-3-yl)-1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-o-
ne
##STR00095##
[0315] The title compound was obtained via Suzuki coupling
according to general procedure A from
8-bromo-1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-one (252 mg,
1.0 mmol) and 5-methoxy-3-pyridineboronic acid (115 mg, 0.75 mmol)
after flash chromatography on silica gel (ethyl acetate,
R.sub.f=0.09) as colorless needles (74 mg, 0.26 mmol, 35%), mp
(ethyl acetate) 172.degree. C. .sup.1H-NMR (500 MHz, CDCl.sub.3):
.delta.=2.70 (t, .sup.3J=7.7 Hz, 2H), 3.02 (t, .sup.3J=7.7 Hz, 2H),
3.23 (t, .sup.3J=8.4 Hz, 2H), 3.90 (s, 3H), 4.11 (t, .sup.3J=8.4
Hz, 2H), 7.18 (s, 1H), 7.26 (s, 1H), 7.27 (dd, .sup.4J=2.8 Hz,
.sup.4J=1.9 Hz, 1H), 8.25 (d, .sup.4J=2.8 Hz, 1H), 8.37 (d,
.sup.4J=1.9 Hz, 1H). .sup.13C-NMR (125 MHz, CDCl.sub.3):
.delta.=24.4, 27.7, 31.5, 45.4, 55.6, 118.8, 120.6, 122.4, 124.8,
129.8, 133.3, 135.6, 137.4, 140.5, 141.6, 155.7, 167.5. MS m/z
281.13 (MH.sup.+).
Example 18
8-Isoquinolin-4-yl-1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-one
##STR00096##
[0317] The title compound was obtained via Suzuki coupling
according to general procedure A from
8-bromo-1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-one (252 mg,
1.0 mmol) and 4-isoquinolineboronic acid (227 mg, 0.9 mmol) after
flash chromatography on silica gel (hexanes/ethyl acetate, 2/3,
R.sub.f=0.13) as colorless needles (93 mg, 0.31 mmol, 34%), mp
(hexanes/ethyl acetate) 185.degree. C. .sup.1H-NMR (500 MHz,
CDCl.sub.3): .delta.=2.75 (t, .sup.3J=7.8 Hz, 2H), 3.05 (t,
.sup.3J=7.8 Hz, 2H), 3.28 (t, .sup.3J=8.4 Hz, 2H), 4.16 (t,
.sup.3J=8.4 Hz, 2H), 7.13 (s, 1H), 7.20 (s, 1H), 7.62 (m, 1H), 7.67
(m, 1H), 7.91 (d, .sup.3J=8.5 Hz, 1H), 8.02 (d, .sup.3J=7.9 Hz,
1H), 8.44 (s, 1H), 9.22 (s, 1H). .sup.13C-NMR (125 MHz,
CDCl.sub.3): .delta.=24.4, 27.8, 31.6, 45.4, 120.2, 124.7, 125.1,
127.1, 127.4, 127.9, 128.4, 129.3, 130.5, 132.2, 133.2, 134.2,
141.3, 142.8, 151.8, 167.6. MS m/z 301.15 (MH.sup.+).
Example 19
9-(5-Methoxypyridin-3-yl)-1,2,6,7-tetrahydro-5H-pyrido[3,2,1-ij]quinolin-3-
-one
##STR00097##
[0319] The title compound was obtained via Suzuki coupling
according to general procedure A from
9-bromo-1,2,6,7-tetrahydro-5H-pyrido[3,2,1-ij]quinolin-3-one (266
mg, 1.0 mmol) and 5-methoxy-3-pyridineboronic acid (115 mg, 0.75
mmol) after flash chromatography on silica gel (hexanes/ethyl
acetate, 2/3, R.sub.f=0.08) and crystallization from
acetone/diethylether as colorless needles (63 mg, 0.21 mmol, 28%),
mp (acetone/diethylether) 150.degree. C. .sup.1H-NMR (500 MHz,
CDCl.sub.3): .delta.=1.98 (m, 2H), 2.69 (m, 2H), 2.86 (t,
.sup.3J=6.3 Hz, 2H), 2.95 (m, 2H), 3.90 (t, .sup.3J=6.0 Hz, 2H),
3.91 (s, 3H), 7.20 (s, 1H), 7.21 (s, 1H), 7.31 (dd, .sup.4J=2.8 Hz,
.sup.4J=1.9 Hz, 1H), 8.26 (d, .sup.4J=2.8 Hz, 1H), 8.41 (d,
.sup.4J=1.9 Hz, 1H). .sup.13C-NMR (125 MHz, CDCl.sub.3):
.delta.=21.4, 25.4, 27.5, 31.4, 40.0, 55.7, 118.7, 124.5, 125.9,
126.1, 126.5, 131.7, 135.8, 136.3, 136.6, 140.4, 155.8, 169.4. MS
m/z 295.06 (MH.sup.+).
Example 20
9-Isoquinolin-4-yl-1,2,6,7-tetrahydro-5H-pyrido[3,2,1-ij]quinolin-3-one
##STR00098##
[0321] The title compound was obtained via Suzuki coupling
according to general procedure A from
9-bromo-1,2,6,7-tetrahydro-5H-pyrido[3,2,1-ij]quinolin-3-one (266
mg, 1.0 mmol) and 4-isoquinolineboronic acid (227 mg, 0.9 mmol)
after flash chromatography on silica gel (hexanes/ethyl acetate,
2/3, R.sub.f=0.10) and crystallization from acetone/diethylether as
colorless needles (173 mg, 0.55 mmol, 61%), mp
(acetone/diethylether) 159.degree. C. .sup.1H-NMR (500 MHz,
CDCl.sub.3): .delta.=2.01 (m, 2H), 2.72 (m, 2H), 2.87 (t,
.sup.3J=6.3 Hz, 2H), 2.97 (m, 2H), 3.95 (t, .sup.3J=6.0 Hz, 2H),
7.14 (s, 1H), 7.15 (s, 1H), 7.62 (m, 1H), 7.68 (m, 1H), 7.94 (d,
.sup.3J=8.5 Hz, 1H), 8.03 (d, .sup.3J=7.9 Hz, 1H), 8.45 (s, 1H),
9.23 (s, 1H). .sup.13C-NMR (125 MHz, CDCl.sub.3): .delta.=21.4,
25.3, 27.4, 31.5, 40.0, 124.7, 125.5, 125.6, 127.1, 127.4, 127.9,
128.4, 129.3, 130.5, 131.1, 132.6, 134.2, 136.0, 142.8, 151.9,
169.5. MS m/z 315.01 (MH.sup.+).
Example 21
6-Pyrimidin-5-yl-3,4-dihydro-1H-quinolin-2-one
##STR00099##
[0323] The title compound was obtained via Suzuki coupling
according to general procedure A from
6-Bromo-3,4-dihydro-1H-quinolin-2-one (226 mg, 1.0 mmol) and
5-pyrimidineboronic acid (103 mg, 0.83 mmol) after crystallization
from ethanol as colorless needles (75 mg, 0.33 mmol, 40%), mp
(ethanol) 233.degree. C. .sup.1H-NMR (500 MHz, CDCl.sub.3):
.delta.=2.50 (t, .sup.3J=7.6 Hz, 2H), 2.95 (t, .sup.3J=7.6 Hz, 2H),
6.98 (d, .sup.3J=8.2 Hz, 1H), 7.59 (dd, .sup.3J=8.2 Hz, .sup.4J=1.6
Hz, 1H), 7.66 (d, .sup.4J=1.6 Hz, 1H), 9.08 (s, 2H), 9.11 (s, 1H),
10.22 (s, 1H). .sup.13C-NMR (125 MHz, CDCl.sub.3): .delta.=24.8,
30.2, 115.7, 124.5, 125.6, 126.2, 127.1, 132.9, 139.1, 154.0,
156.6, 170.2. MS m/z 225.74 (MH.sup.+).
Example 22
8-Pyridin-3-yl-1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinoline-4-thione
##STR00100##
[0325] A mixture of
8-pyridin-3-yl-1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinoline-4-one
(900 mg, 3.60 mmol) and Lawessons reagent (1.45 g, 3.60 mmol) was
refluxed in a mixture of 50 ml toluene and 5 ml THF for 2 h. After
evaporation of the solvent under reduced pressure, the residue was
purified by flash chromatography on silica gel (hexanes/ethyl
acetate, 1/1, R.sub.f=0.25).
8-Pyridin-3-yl-1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinoline-4-thione
was obtained as a yellow solid (155 mg, 0.58 mmol, 26%), mp (HCl
salt, THF) 283.degree. C. .sup.1H-NMR (500 MHz, CDCl.sub.3):
.delta.=2.96 (t, .sup.3J=7.9 Hz, 2H), 3.25 (t, .sup.3J=7.6 Hz, 2H),
3.29 (t, .sup.3J=8.0 Hz, 2H), 4.42 (t, .sup.3J=8.2 Hz, 2H), 7.23
(s, 1H), 7.33 (s, 1H), 7.34 (ddd, .sup.3J=7.9 Hz, .sup.3J=4.7 Hz,
.sup.5J=0.6 Hz, 1H), 7.81 (ddd, .sup.3J=7.9 Hz, .sup.4J=2.5 Hz,
.sup.4J=1.9 Hz, 1H), 8.57 (dd, .sup.3J=4.7 Hz, .sup.4J=1.6 Hz, 1H),
8.59 (d, .sup.4J=2.2 Hz, 1H). .sup.13C-NMR (125 MHz, CDCl.sub.3):
.delta.=23.5, 27.1, 40.3, 52.0, 122.7, 123.0, 123.6, 125.1, 131.7,
134.2, 135.2, 136.4, 139.6, 148.1, 148.5, 192.5. MS m/z 267.10
(MH.sup.+).
[0326] According to Example 22 starting from substituted
8-pyridin-3-yl-1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-one
derivatives (see Schemes 1-19) the following compounds can be
synthesized:
##STR00101## ##STR00102## ##STR00103## ##STR00104## ##STR00105##
##STR00106## ##STR00107## ##STR00108##
[0327] According to Example 22 further tricyclic carbonyl
compounds, as described in Example 14, can be derivatized to the
corresponding thio analogues.
##STR00109## ##STR00110##
[0328] Further thio analogues which can be synthesized according to
Example 22 starting from the carbonyl compounds described in
Example 35:
##STR00111## ##STR00112## ##STR00113## ##STR00114##
Example 23
8-(5-Hydroxypyridin-3-yl)-1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-o-
ne
##STR00115##
[0330] A solution of
8-(5-methoxypyridin-3-yl)-1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4--
one (95 mg, 0.34 mmol) in 35 ml concentrated hydrobromic acid was
heated under reflux for 18 h. After cooling to room temperature,
the reaction mixture was neutralized with saturated NaHCO.sub.3
solution and extracted with ethyl acetate (3.times.100 ml). The
crude product which was obtained after evaporation of the solvent
was purified by flash chromatography on silica gel (ethyl acetate,
R.sub.f=0.11) and crystallization from ethanol, yielding the
hydroxy compound as a colorless solid (75 mg, 0.28 mmol, 83%), mp
(HCl salt, THF)>300.degree. C. .sup.1H-NMR (500 MHz,
DMSO-d.sub.6): .delta.=2.57 (t, .sup.3J=7.7 Hz, 2H), 2.97 (t,
.sup.3J=7.7 Hz, 2H), 3.18 (t, .sup.3J=8.3 Hz, 2H), 3.96 (t,
.sup.3J=8.3 Hz, 2H), 7.28 (dd, .sup.4J=2.5 Hz, .sup.4J=1.9 Hz, 1H),
7.31 (s, 1H), 7.37 (s, 1H), 8.06 (d, .sup.4J=2.5 Hz, 1H), 8.25 (d,
.sup.4J=1.9 Hz, 1H). MS m/z 267.94 (MH.sup.+).
Example 24
6,6-Dimethyl-8-pyridin-3-yl-1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-
-one
##STR00116##
[0332] The title compound was obtained via Suzuki coupling
according to general procedure A from
8-bromo-6,6-dimethyl-1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-one
(280 mg, 1.0 mmol) (prepared previously from
3,3-dimethylacryloylchloride and indoline as described for
8-bromo-1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-one and
9-bromo-1,2,6,7-tetrahydro-5H-pyrido[3,2,1-ij]quinolin-3-one) and
3-pyridineboronic acid (92 mg, 0.75 mmol) after flash
chromatography on silica gel (hexanes/ethyl acetate, 1/9,
R.sub.f=0.09) and crystallization from acetone as colorless needles
(48 mg, 0.17 mmol, 23%), mp (acetone) 180.degree. C. .sup.1H-NMR
(500 MHz, CDCl.sub.3): .delta.=1.35 (s, 6H), 2.55 (s, 2H), 3.27 (t,
.sup.3J=8.3 Hz, 2H), 4.14 (t, .sup.3J=8.3 Hz, 2H), 7.25 (d,
.sup.4J=1.3 Hz, 1H), 7.28 (d, .sup.4J=1.6 Hz, 1H), 7.33 (ddd,
.sup.3J=7.9 Hz, .sup.3J=4.7 Hz, .sup.5J=1.0 Hz, 1H), 7.80 (ddd,
.sup.3J=7.9 Hz, .sup.4J=2.2 Hz, .sup.4J=1.6 Hz, 1H), 8.55 (dd,
.sup.3J=4.7 Hz, .sup.4J=1.6 Hz, 1H), 8.78 (dd, .sup.4J=2.5 Hz,
.sup.5J=1.0 Hz, 1H). .sup.13C-NMR (125 MHz, CDCl.sub.3):
.delta.=28.0, 35.0, 45.1, 46.8, 121.5, 122.5, 123.5, 130.1, 130.2,
134.0, 134.1, 137.0, 140.2, 148.1, 148.2, 167.2. MS m/z 279.14
(MH.sup.+).
Example 25
8-(5-Ethoxypyridin-3-yl)-1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-on-
e
##STR00117##
[0334] The title compound was obtained via Suzuki coupling
according to general procedure B from
8-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2,5,6-tetrahydro-pyrro-
lo[3,2,1-ij]quinolin-4-one (300 mg, 1.0 mmol) and
3-bromo-5-ethoxypyridine (242 mg, 1.2 mmol) after flash
chromatography on silica gel (hexanes/ethyl acetate, 1/9,
R.sub.f=0.10) and crystallization from acetone/diethylether as
colorless needles (132 mg, 0.45 mmol, 45%), mp
(acetone/diethyl-ether) 172.degree. C. .sup.1H-NMR (500 MHz,
CDCl.sub.3): .delta.=1.46 (t, .sup.3J=7.3 Hz, 3H), 2.72 (t,
.sup.3J=7.7 Hz, 2H), 3.03 (t, .sup.3J=7.7 Hz, 2H), 3.24 (t,
.sup.3J=8.5 Hz, 2H), 4.11-4.16 (m, 4H) 7.19 (s, 1H), 7.27 (s, 1H),
7.28 (dd, .sup.4J=2.5 Hz, .sup.4J=1.9 Hz, 1H), 8.24 (d, .sup.4J=2.5
Hz, 1H), 8.37 (d, .sup.4J=1.9 Hz, 1H). .sup.13C-NMR (125 MHz,
CDCl.sub.3): .delta.=14.8, 24.5, 27.7, 31.6, 45.5, 64.0, 119.5,
120.6, 122.4, 124.8, 129.8, 133.4, 136.1, 137.4, 140.4, 141.6,
155.1, 167.6. MS m/z 295.16 (MH.sup.+).
Example 26
8-(5-Trifluoromethylpyridin-3-yl)-1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quin-
olin-4-one
##STR00118##
[0336] The title compound was obtained via Suzuki coupling
according to general procedure B from
8-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2,5,6-tetrahydro-pyrro-
lo[3,2,1-ij]quinolin-4-one (329 mg, 1.1 mmol) and
3-bromo-5-(trifluoromethyl)pyridine (249 mg, 1.1 mmol) after flash
chromatography on silica gel (hexanes/ethyl acetate, 1/1,
R.sub.f=0.14) and crystallization from acetone/diethylether as
colorless needles (248 mg, 0.78 mmol, 71%), mp
(acetone/diethylether) 212.degree. C. .sup.1H-NMR (500 MHz,
CDCl.sub.3): .delta.=2.73 (t, .sup.3J=7.7 Hz, 2H), 3.05 (t,
.sup.3J=7.9 Hz, 2H), 3.27 (t, .sup.3J=8.5 Hz, 2H), 4.15 (t,
.sup.3J=8.5 Hz, 2H), 7.23 (s, 1H), 7.30 (s, 1H), 8.01 (m, 1H), 8.81
(d, .sup.4J=1.3 Hz, 1H), 8.95 (d, .sup.4J=1.9 Hz, 1H). MS m/z
318.95 (MH.sup.+).
Example 27
8-(5-Fluoropyridin-3-yl)-1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-on-
e
##STR00119##
[0338] The title compound was obtained via Suzuki coupling
according to general procedure B from
8-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2,5,6-tetrahydro-pyrro-
lo[3,2,1-ij]quinolin-4-one (359 mg, 1.2 mmol) and
3-bromo-5-fluoropyridine (211 mg, 1.2 mmol) after flash
chromatography on silica gel (hexanes/ethyl acetate, 1/1,
R.sub.f=0.09) and crystallization from acetone/diethylether as
colorless needles (202 mg, 0.75 mmol, 63%), mp
(acetone/diethyl-ether) 158.degree. C. .sup.1H-NMR (500 MHz,
CDCl.sub.3): .delta.=2.72 (t, .sup.3J=7.7 Hz, 2H), 3.04 (t,
.sup.3J=7.9 Hz, 2H), 3.25 (t, .sup.3J=8.5 Hz, 2H), 4.14 (t,
.sup.3J=8.8 Hz, 2H), 7.20 (s, 1H), 7.28 (s, 1H), 7.51 (m, 1H), 8.41
(d, .sup.4J=2.5 Hz, 1H), 8.60 (s, 1H). .sup.13C-NMR (125 MHz,
CDCl.sub.3): .delta.=24.5, 27.7, 31.5, 45.5, 120.7 (q,
.sup.2J.sub.C,F=18.3 Hz), 120.8, 122.5, 124.9, 130.1, 131.9, 136.2
(q, .sup.2J.sub.C,F=22.9 Hz) 138.4, 142.1, 143.9, 159.7 (q,
.sup.1J.sub.C,F=257 Hz), 167.5. MS m/z 269.38 (MH.sup.+).
Example 28
8-Imidazol-1-yl-1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-one
##STR00120##
[0340] Imidazole (628 mg, 9.23 mmol),
8-bromo-1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-one (2.12 g,
8.39 mmol), potassium carbonate (1.28 g, 9.23 mmol) and
copper(II)sulfate (160 mg, 1.0 mmol) were mixed and heated at
180.degree. C. for 10 h under an atmosphere of dry nitrogen. After
being cooled to room temperature, the reaction mixture was poured
into 150 ml water and extracted with ethyl acetate (3.times.100
ml). After drying over MgSO.sub.4 and evaporating of the solvent,
the crude product was purified by two subsequent crystallizations
from acetone to yield a colorless solid (674 mg, 2.82 mg, 34%). mp
(acetone) 124.degree. C. .sup.1H-NMR (500 MHz, CDCl.sub.3):
.delta.=2.70 (t, .sup.3J=7.7 Hz, 2H), 3.01 (t, .sup.3J=7.7 Hz, 2H),
3.23 (t, .sup.3J=8.5 Hz, 2H), 4.13 (t, .sup.3J=8.5 Hz, 2H), 7.01
(s, 1H), 7.08 (s, 1H), 7.18 (m, 2H), 7.75 (s, 1H). MS m/z 239.95
(MH.sup.+).
Example 29
8-Pyridin-4-yl-1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-one
##STR00121##
[0342] The title compound was obtained via Suzuki coupling
according to general procedure B from
8-bromo-1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-one (627 mg,
3.50 mmol) and 4-pyridineboronic acid (369 mg, 3.0 mmol) after
crystallization from ethanol as yellow crystals (225 mg, 0.90 mmol,
30%), mp (ethanol) 174.degree. C. .sup.1H-NMR (500 MHz,
DMSO-d.sub.6): .delta.=2.58 (t, .sup.3J=7.7 Hz, 2H), 2.98 (t,
.sup.3J=7.9 Hz, 2H), 3.19 (t, .sup.3J=8.5 Hz, 2H), 3.98 (t,
.sup.3J=8.8 Hz, 2H), 7.50 (s, 1H), 7.55 (s, 1H), 7.62 (d,
.sup.3J=5.3 Hz, 2H), 8.55 (d, .sup.3J=5.1 Hz, 2H). .sup.13C-NMR
(125 MHz, DMSO-d.sub.6): .delta.=23.7, 27.1, 31.0, 45.2, 120.5,
120.7, 121.8, 124.2, 129.9, 131.9, 142.4, 147.2, 150.0, 166.8. MS
m/z 251.71 (MH.sup.+).
Example 30
8-Pyrimidin-5-yl-1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-one
##STR00122##
[0344] The title compound was obtained via Suzuki coupling
according to general procedure B from
8-bromo-1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-one (627 mg,
3.50 mmol) and 5-pyrimidineboronic acid (372 mg, 3.0 mmol) after
crystallization from acetone as a yellow crystals (324 mg, 1.29
mmol, 43%), mp (acetone) 186.degree. C. .sup.1H-NMR (500 MHz,
DMSO-d.sub.6): .delta.=2.59 (t, .sup.3J=7.7 Hz, 2H), 2.98 (t,
.sup.3J=7.9 Hz, 2H), 3.20 (t, .sup.3J=8.5 Hz, 2H), 3.98 (t,
.sup.3J=8.5 Hz, 2H), 7.49 (s, 1H), 7.54 (s, 1H), 9.05 (s, 2H), 9.10
(s, 1H). .sup.13C-NMR (125 MHz, DMSO-d.sub.6): .delta.=23.7, 27.1,
31.0, 45.2, 120.8, 121.9, 124.3, 128.4, 130.0, 133.5, 142.1, 154.2,
156.5, 166.8. MS m/z 251.85 (MH.sup.+).
Example 31
8-(Pyridine-4-carbonyl)-1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-one
##STR00123##
[0346] To a molten mixture of AlCl.sub.3 (8.0 g, 60.0 mmol) and
NaCl (2.34 g, 40.0 mmol) at 150.degree. C. was added
1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-one (1.79 g, 10.0
mmol) and thereafter isonicotinoylchloride hydrochloride salt (1.96
g, 11.0 mmol) portionwise. After stirring for 15 min and cooling to
room temperature, excess aluminum chloride was decomposed by the
addition of a chilled mixture of 10 ml concentrated hydrochloric
acid and 200 ml water. Neutralization with NaHCO.sub.3 solution and
subsequent extraction with ethyl acetate (3.times.100 ml), followed
by drying over MgSO.sub.4 and removal of the solvent gave the crude
product. Purification by crystallization from acetone gave the
acylation product (751 mg, 2.70 mmol, 27%) as a yellow solid, mp
(acetone) 184.degree. C. .sup.1H-NMR (500 MHz, CDCl.sub.3):
.delta.=2.70 (t, .sup.3J=7.7 Hz, 2H), 2.99 (t, .sup.3J=7.8 Hz, 2H),
3.21 (t, .sup.3J=8.2 Hz, 2H), 4.12 (t, .sup.3J=8.2 Hz, 2H), 7.49
(m, 3H), 7.55 (s, 1H), 8.76 (d, .sup.3J=5.1 Hz, 2H). .sup.13C-NMR
(125 MHz, CDCl.sub.3): .delta.=24.1, 27.2, 31.3, 45.7, 119.9,
122.6, 126.1, 129.0, 129.4, 131.4, 145.3, 146.3, 150.2, 167.8,
193.9. MS m/z 279.07 (MH.sup.+).
Example 32
8-(Pyridine-3-carbonyl)-1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-one
##STR00124##
[0348] To a molten mixture of AlCl.sub.3 (8.0 g, 60.0 mmol) and
NaCl (2.34 g, 40.0 mmol) at 150.degree. C. was added
1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-one (1.79 g, 10.0
mmol) and thereafter nicotinoylchloride hydrochloride salt (1.96 g,
11.0 mmol) portionwise. After stirring for 15 min and cooling to
room temperature, excess aluminum chloride was decomposed by the
addition of a chilled mixture of 10 ml concentrated hydrochloric
acid and 200 ml water. Neutralization with NaHCO.sub.3 solution and
subsequent extraction with ethyl acetate (3.times.100 ml), followed
by drying over MgSO.sub.4 and removal of the solvent gave the crude
product. Purification by crystallization from ethanol gave the
acylation product (624 mg, 2.24 mmol, 22%) as a yellow solid, mp
(ethanol) 147.degree. C. .sup.1H-NMR (500 MHz, CDCl.sub.3):
.delta.=2.72 (t, .sup.3J=7.9 Hz, 2H), 3.02 (t, .sup.3J=7.9 Hz, 2H),
3.23 (t, .sup.3J=8.6 Hz, 2H), 4.14 (t, .sup.3J=8.6 Hz, 2H), 7.44
(ddd, .sup.3J=7.9 Hz, .sup.3J=4.7 Hz, .sup.5J=1.0 Hz, 1H), 7.53 (s,
1H), 7.58 (s, 1H), 8.06 (m, 1H), 8.78 (dd, .sup.3J=5.0 Hz,
.sup.4J=1.9 Hz, 1H), 8.92 (dd, .sup.4J=1.9 Hz, .sup.5J=0.8 Hz, 1H).
.sup.13C-NMR (125 MHz, CDCl.sub.3): .delta.=24.2, 27.3, 31.4, 45.8,
199.9, 123.4, 126.1, 128.9, 129.4, 132.3, 134.0, 137.0, 146.1,
150.4, 152.4, 167.8, 193.6. MS m/z 278.79 (MH.sup.+).
Example 33
8-(5-Phenylpyridin-3-yl)-1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-on-
e
##STR00125##
[0350] The title compound was obtained via Suzuki coupling
according to general procedure B from
8-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2,5,6-tetrahydro-pyrro-
lo[3,2,1-ij]quinolin-4-one (325 mg, 1.07 mmol) and
3-bromo-5-phenylpyridine (301 mg, 1.28 mmol) after flash
chromatography on silica gel (hexanes/ethyl acetate, 2/3,
R.sub.f=0.09) as colorless plates (150 mg, 0.46 mmol, 43%), mp
(hexanes/ethyl acetate) 189.degree. C. .sup.1H-NMR (500 MHz,
CDCl.sub.3): .delta.=2.73 (t, .sup.3J=7.7 Hz, 2H), 3.05 (t,
.sup.3J=7.9 Hz, 2H), 3.26 (t, .sup.3J=8.5 Hz, 2H), 4.14 (t,
.sup.3J=8.5 Hz, 2H), 7.26 (s, 1H), 7.34 (s, 1H), 7.42 (m, 1H), 7.49
(m, 2H), 7.63 (dd, .sup.3J=6.9 Hz, .sup.4J=1.6 Hz, 2H), 7.98 (m,
1H), 8.75 (d, .sup.4J=1.9 Hz, 1H), 8.78 (d, .sup.4J=1.9 Hz, 1H).
.sup.13C-NMR (125 MHz, CDCl.sub.3): .delta.=24.5, 27.8, 31.6, 45.5,
120.7, 122.4, 124.8, 127.2, 128.3, 129.1, 129.9, 132.7, 133.3,
136.7, 136.8, 137.7, 141.7, 146.5, 146.6, 167.5. MS m/z 326.86
(MH.sup.+).
Example 34
8-(5-Isopropoxypyridin-3-yl)-1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin--
4-one
##STR00126##
[0352] The title compound was obtained via Suzuki coupling
according to general procedure B from
8-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2,5,6-tetrahydro-pyrro-
lo[3,2,1-ij]quinolin-4-one (359 mg, 1.20 mmol) and
3-bromo-5-(1-methylethoxy)pyridine (281 mg, 1.30 mmol) after flash
chromatography on silica gel (hexanes/ethyl acetate, 3/7,
R.sub.f=0.07) as colorless plates (196 mg, 0.63 mmol, 53%), mp
(hexanes/ethyl acetate) 155.degree. C. .sup.1H-NMR (500 MHz,
CDCl.sub.3): .delta.=1.38 (d, .sup.3J=6.3 Hz, 6H), 2.72 (t,
.sup.3J=7.6 Hz, 2H), 3.03 (t, .sup.3J=7.9 Hz, 2H), 3.24 (t,
.sup.3J=8.5 Hz, 2H), 4.13 (t, .sup.3J=8.5 Hz, 2H), 4.65 (sep,
.sup.3J=6.3 Hz, 1H), 7.19 (s, 1H), 7.26 (s, 1H), 7.30 (m, 1H), 8.21
(d, .sup.4J=2.8 Hz, 1H), 8.35 (d, .sup.4J=1.6 Hz, 1H). .sup.13C-NMR
(125 MHz, CDCl.sub.3): .delta.=22.0, 24.5, 27.7, 31.6, 45.5, 70.8,
120.6, 121.2, 122.4, 124.8, 129.9, 133.2, 136.8, 137.6, 139.9,
141.7, 154.2, 167.6. MS m/z 308.87 (MH.sup.+).
Example 35
8-(1-Imidazol-1-yl-ethyl)-1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-o-
ne
##STR00127##
[0354] To a solution of
1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-one (1.79 g, 10.0
mmol) and AlCl.sub.3 (9.31 g, 70.0 mmol) in 50 ml dry
dichloromethane was added dropwise acetyl chloride (1.18 g, 15.0
mmol) at room temperature. The mixture was then refluxed for 18 h,
cooled to ambient temperature and quenched by addition of a cold
mixture of 10 ml concentrated hydrochloric acid and 20 ml water.
Extraction with ethyl acetate (3.times.100 ml), followed by drying
over MgSO.sub.4 and removal of the solvent in vacuo gave the crude
product. This was dissolved in 50 ml methanol and sodium boron
hydride (452 mg, 12.0 mmol) was added portionwise at 0.degree. C.
After 1 h stirring, water was added and the mixture was extracted
with ethyl acetate (3.times.100 ml). Drying over MgSO.sub.4 and
removal of the solvent gave the alcohol as crude product. A
solution of the obtained alcohol in 10 ml dry THF was added to a
solution of thionylbis(imidazole) (prepared previously by reaction
of imidazole (4.52 g, 66.4 mmol) with thionyl chloride (1.97 g,
16.6 mmol) in 30 mL THF and filtration to remove precipitated
imidazole hydrochloride) at 0.degree. C. The reaction mixture was
stirred for one hour at 0.degree. C. and an additional 18 h at
ambient temperature. Water was added and the mixture extracted with
ethyl acetate (3.times.100 ml), the combined organic extracts
washed with water and brine, and the solvent was removed in vacuo
after drying over MgSO.sub.4. The crude product was purified by two
subsequent crystallizations from acetone to yield
8-(1-Imidazol-1-yl-ethyl)-1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quino-
lin-4-one (488 mg, 1.83 mmol, 18%) as pale yellow crystals, mp
(acetone) 197.degree. C. .sup.1H-NMR (500 MHz, CDCl.sub.3):
.delta.=1.82 (d, .sup.3J=6.9 Hz, 3H), 2.65 (t, .sup.3J=7.7 Hz, 2H),
2.92 (t, .sup.3J=7.7 Hz, 2H), 3.14 (t, .sup.3J=8.5 Hz, 2H), 4.07
(t, .sup.3J=8.5 Hz, 2H), 5.27 (q, .sup.3J=6.9 Hz, 1H), 6.79 (s,
1H), 6.85 (s, 1H), 6.91 (s, 1H), 7.07 (s, 1H), 7.58 (s, 1H).
.sup.13C-NMR (125 MHz, CDCl.sub.3): .delta.=22.3, 24.4, 27.7, 31.5,
45.4, 56.6, 117.9, 120.4, 121.2, 123.5, 129.3, 129.6, 135.9, 136.9,
141.4, 167.5. MS m/z 267.94 (MH.sup.+).
[0355] According to Example 35 starting from
1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-4-one the following
compounds can be synthesized by reacting with various carboxylic
acid halogenides (see Schemes 1-19):
##STR00128## ##STR00129## ##STR00130## ##STR00131##
Example 36
8-[5-(4-Fluorophenyl)-pyridin-3-yl]-1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]qu-
inolin-4-one
##STR00132##
[0357] The title compound was obtained via Suzuki coupling
according to general procedure B from
8-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2,5,6-tetrahydro-pyrro-
lo[3,2,1-ij]quinolin-4-one (463 mg, 1.55 mmol) and
3-bromo-5-(4-fluorophenyl)pyridine (440 mg, 1.75 mmol) (prepared
previously by Suzuki coupling according to general procedure B from
3,5-dibromopyridine and 4-fluorophenylboronic acid) after flash
chromatography on silica gel (hexanes/ethyl acetate, 2/3,
R.sub.f=0.05) as colorless needles (189 mg, 0.55 mmol, 35%), mp
(hexanes/ethyl acetate) 233.degree. C. .sup.1H-NMR (500 MHz,
CDCl.sub.3): .delta.=2.73 (t, .sup.3J=7.7 Hz, 2H), 3.05 (t,
.sup.3J=7.7 Hz, 2H), 3.26 (t, .sup.3J=8.5 Hz, 2H), 4.14 (t,
.sup.3J=8.5 Hz, 2H), 7.18 (m, 2H), 7.26 (s, 1H), 7.33 (s, 1H), 7.58
(m, 2H), 7.93 (m, 1H), 8.73 (d, .sup.4J=2.2 Hz, 1H), 8.74 (d,
.sup.4J=1.9 Hz, 1H). .sup.13C-NMR (125 MHz, CDCl.sub.3):
.delta.=24.5, 27.7, 31.6, 45.5, 116.1 (d, .sup.2J.sub.C,F=22.0 Hz),
120.8, 122.4, 124.8, 128.9 (d, .sup.3J.sub.C,F=8.3 Hz), 130.0,
132.5, 133.1, 133.8, 133.8, 136.8, 141.8, 146.2, 146.6, 163.0 (d,
.sup.1J.sub.C,F=248 Hz), 167.5. MS m/z 344.84 (MH.sup.+).
Example 37
8-[5-(3-Fluorophenyl)-pyridin-3-yl]-1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]qu-
inolin-4-one
##STR00133##
[0359] The title compound was obtained via Suzuki coupling
according to general procedure B from
8-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2,5,6-tetrahydro-pyrro-
lo[3,2,1-ij]quinolin-4-one (360 mg, 1.20 mmol) and
3-bromo-5-(3-fluorophenyl)pyridine (378 mg, 1.50 mmol) (prepared
previously by Suzuki coupling according to general procedure B from
3,5-dibromopyridine and 3-fluorophenylboronic acid) after flash
chromatography on silica gel (hexanes/ethyl acetate, 2/3, R.sub.f
0.08) as colorless needles (97 mg, 0.28 mmol, 23%), mp
(hexanes/ethyl acetate) 181.degree. C. .sup.1H-NMR (500 MHz,
CDCl.sub.3): .delta.=2.73 (t, .sup.3J=7.9 Hz, 2H), 3.05 (t,
.sup.3J=7.9 Hz, 2H), 3.27 (t, .sup.3J=8.5 Hz, 2H), 4.14 (t,
.sup.3J=8.5 Hz, 2H), 7.12 (m, 1H), 7.26 (s, 1H), 7.31-7.35 (m, 2H),
7.40-7.48 (m, 2H), 7.96 (m, 1H), 8.76 (d, .sup.4J=2.0 Hz, 1H), 8.77
(d, .sup.4J=2.2 Hz, 1H). .sup.13C-NMR (125 MHz, CDCl.sub.3):
.delta.=24.5, 27.7, 31.6, 45.5, 120.8, 114.2 (d,
.sup.2J.sub.C,F=22.0 Hz), 115.2 (d, .sup.2J.sub.C,F=21.9 Hz),
122.5, 122.9, 124.8, 130.0, 130.7 (.sup.3J.sub.C,F=8.3 Hz), 132.7,
133.0, 135.5, 136.9, 139.9 (.sup.3J.sub.C,F=7.3 Hz), 141.9, 146.2,
147.0, 163.3 (d, .sup.1J.sub.C,F=247 Hz), 167.5. MS m/z 344.80
(MH.sup.+).
Example 38
8-[5-(4-Methoxyphenyl)pyridin-3-yl]-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]-qu-
inolin-4-on
##STR00134##
[0361] The title compound was obtained according to general
procedure B from
8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2,5,6-tetrahydro--
pyrrolo[3,2,1-ij]quinolin-4-one (389 mg, 1.30 mmol) and
3-bromo-5-(4-methoxyphenyl)pyridine (315 mg, 1.19 mmol)
(synthesized by Suzuki coupling according to general procedure B
from 3,5-dibromopyridine and 4-methoxyphenylboronic acid) after
flash chromatography (ethyl acetate, R.sub.f=0.08) as a colorless
crystalline solid (182 mg, 0.51 mmol, 43%). .sup.1H-NMR (500 MHz,
CDCl.sub.3): .delta.=2.73 (t, .sup.3J=7.7 Hz, 2H), 3.05 (t,
.sup.3J=7.7 Hz, 2H), 3.26 (t, .sup.3J=8.5 Hz, 2H), 3.86 (s. 3H),
4.14 (t, .sup.3J=8.5 Hz, 2H), 7.02 (d, .sup.3J=8.8 Hz. 2H), 7.26
(s, 1H), 7.33 (s, 1H), 7.56 (d, .sup.3J=8.8 Hz, 2H), 7.92 (m, 1H),
8.70 (d, .sup.4J=2.0 Hz, 1H), 8.74 (d, .sup.4J=2.2 Hz, 1H),
.sup.13C-NMR (125 MHz, CDCl.sub.3): .delta.=24.5, 27.8, 31.6, 45.5,
55.4, 114.6, 120.7, 122.4, 124.8, 128.3, 129.9, 130.2, 132.1,
133.5, 136.2, 136.6, 141.7, 146.2, 147.3, 159.9, 167.6, MS m/z
357.09 (MH.sup.+).
Example 39
8-[5-(3-Methoxyphenyl)pyridin-3-yl]-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]-qu-
inolin-4-one
##STR00135##
[0363] The title compound was obtained according to general
procedure B from
8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2,5,6-tetrahydro--
pyrrolo[3,2,1-ij]quinolin-4-one (329 mg, 1.10 mmol) and
3-bromo-5-(3-methoxyphenyl)pyridine (270 mg, 1.02 mmol)
(synthesized by Suzuki coupling according to general procedure B
from 3,5-dibromopyridine and 4-methoxyphenylboronic acid) after
flash chromatography (ethyl acetate, R.sub.f=0.09) as a colorless
crystalline solid (62 mg, 0.17 mmol, 17%). .sup.1H-NMR (500 MHz,
CDCl.sub.3): .delta.=2.73 (t, .sup.3J=7.7 Hz, 2H), 3.05 (t,
.sup.3J=7.7 Hz, 2H), 3.27 (t, .sup.3J=8.3 Hz, 2H), 3.88 (s, 3H),
4.14 (t, .sup.3J=8.2 Hz, 2H), 6.96 (dd, .sup.3J=8.2 Hz, .sup.4J=2.5
Hz, 1H), 7.15 (m, 1H), 7.21 (m, 1H), 7.26 (s, 1H), 7.34 (s, 1H),
7.41 (m, 1H), 7.96 (m, 1H), 8.75 (d, .sup.4J=2.2 Hz, 1H), 8.77 (d,
.sup.4J=2.2 Hz, 1H), .sup.13C-NMR (125 MHz, CDCl.sub.3):
.delta.=24.5, 27.8, 31.6, 45.5, 55.4, 113.2, 113.4, 119.7, 120.7,
122.4, 124.8, 130.0, 130.2, 132.6, 133.4, 136.5, 136.7, 139.3,
141.7, 146.7, 146.9, 160.2, 167.6.
Example 40
8-[5-(2-Fluorophenyl)pyridin-3-yl]-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quin-
olin-4-one
##STR00136##
[0365] The title compound was obtained according to general
procedure B from
8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2,5,6-tetrahydro--
pyrrolo[3,2,1-ij]quinolin-4-one (389 mg, 1.30 mmol) and
3-bromo-5-(2-fluorophenyl)pyridine (311 mg, 1.23 mmol) (synthesized
by Suzuki coupling according to general procedure B from
3,5-dibromopyridine and 2-fluorophenylboronic acid) after flash
chromatography (hexane/ethyl acetate, 2/3, R.sub.f=0.09) as a
colorless crystalline solid (239 mg, 0.69 mmol, 56%). .sup.1H-NMR
(500 MHz, CDCl.sub.3): .delta.=2.72 (t, .sup.3J=7.7 Hz, 2H), 3.04
(t, .sup.3J=7.7 Hz, 2H), 3.26 (t, .sup.3J=8.3 Hz, 2H), 4.13 (t,
.sup.3J=8.5 Hz, 2H), 7.20 (m, 1H), 7.25 (s, 1H), 7.26 (m, 1H), 7.33
(s, 1H), 7.39 (m, 1H), 7.48 (m, 1H), 7.98 (m, 1H), 8.72 (m, 1H),
8.76 (d, .sup.4J=2.2 Hz, 1H), MS m/z 344.98 (MH.sup.+).
Example 41
8-[5-(3-Trifluoromethylphenyl)pyridin-3-yl]-1,2,5,6-tetrahydropyrrolo[3,2,-
1-ij]quinolin-4-one
##STR00137##
[0367] The title compound was obtained according to general
procedure B from
8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2,5,6-tetrahydro--
pyrrolo[3,2,1-ij]quinolin-4-one (344 mg, 1.15 mmol) and
3-bromo-5-(3-trifluoromethylphenyl)pyridine (330 mg, 1.09 mmol)
(synthesized by Suzuki coupling according to general procedure B
from 3,5-dibromopyridine and 3-trifluoromethylphenylboronic acid)
after flash chromatography (hexane/ethyl acetate, 2/3,
R.sub.f=0.05) as a colorless crystalline solid (276 mg, 0.70 mmol,
64%). .sup.1H-NMR (500 MHz, CDCl.sub.3): .delta.=2.72 (t,
.sup.3J=7.7 Hz, 2H), 3.05 (t, .sup.3J=7.8 Hz, 2H), 3.26 (t,
.sup.3J=8.2 Hz, 2H), 4.14 (t, .sup.3J=8.2 Hz, 2H), 7.26 (s, 1H),
7.34 (s, 1H), 7.61 (dd, .sup.3J=7.9 Hz, .sup.3J=7.9 Hz, 1H), 7.68
(d, .sup.3J=7.9 Hz, 1H), 7.80 (d, .sup.3J=7.9 Hz, 1H), 7.85 (s,
1H), 7.96 (m, 1H), 8.77 (d, .sup.4J=1.9 Hz, 1H), 8.79 (d,
.sup.4J=2.2 Hz, 1H), MS m/z 394.94 (MH.sup.+).
Example 42
8-[5-(3,4-Difluorophenyl)pyridin-3-yl]-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]-
quinolin-4-one
##STR00138##
[0369] The title compound was obtained according to general
procedure B from
8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2,5,6-tetrahydro--
pyrrolo[3,2,1-ij]quinolin-4-one (449 mg, 1.50 mmol) and
3-bromo-5-(3,4-difluorophenyl)pyridine (367 mg, 1.34 mmol)
(synthesized by Suzuki coupling according to general procedure B
from 3,5-dibromopyridine and 3,4-difluorophenylboronic acid) after
flash chromatography (hexane/ethyl acetate, 1/4, R.sub.f=0.07) as a
colorless crystalline solid (110 mg, 0.30 mmol, 22%). .sup.1H-NMR
(500 MHz, CDCl.sub.3): .delta.=2.73 (t, .sup.3J=7.6 Hz, 2H), 3.05
(t, .sup.3J=7.6 Hz, 2H), 3.26 (t, .sup.3J=8.5 Hz, 2H), 4.14 (t,
.sup.3J=8.8 Hz, 2H), 7.25 (s, 1H), 7.27-7.36 (m, 3H), 7.43 (m, 1H),
789 (m, 1H), 8.70 (d, .sup.4J=2.2 Hz, 1H), 8.76 (d, .sup.4J=2.2 Hz,
1H), MS m/z 363.11 (MH.sup.+).
Example 43
8-[5-(3-Trifluoromethoxyphenyl)pyridin-3-yl]-1,2,5,6-tetrahydropyrrolo-[3,-
2,1-ij]-quinolin-4-one
##STR00139##
[0371] The title compound was obtained according to general
procedure B from
8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2,5,6-tetrahydro--
pyrrolo[3,2,1-ij]quinolin-4-one (382 mg, 1.20 mmol) and
3-bromo-5-(3-trifluoromethoxyphenyl)pyridine (370 mg, 1.16 mmol)
(synthesized by Suzuki coupling according to general procedure B
from 3,5-dibromopyridine and 3-trifluoromethoxyphenylboronic acid)
after flash chromatography (hexane/ethyl acetate, 1/4,
R.sub.f=0.11) as a colorless crystalline solid (332 mg, 0.81 mmol,
70%). .sup.1H-NMR (500 MHz, CDCl.sub.3): .delta.=2.73 (t,
.sup.3J=7.7 Hz, 2H), 3.06 (t, .sup.3J=7.7 Hz, 2H), 3.27 (t,
.sup.3J=8.5 Hz, 2H), 4.15 (t, .sup.3J=8.5 Hz, 2H), 7.25-7.29 (m,
2H), 7.34 (s, 1H), 7.46 (s, 1H), 7.51-7.57 (m, 2H), 7.94 (m, 1H),
8.76 (d, .sup.4J=2.2 Hz, 1H), 8.79 (d, .sup.4J=2.2 Hz, 1H).
Example 44
8-[5-(2-Methoxyphenyl)pyridin-3-yl]-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]-qu-
inolin-4-one
##STR00140##
[0373] The title compound was obtained according to general
procedure B from
8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2,5,6-tetrahydro--
pyrrolo[3,2,1-ij]quinolin-4-one (512 mg, 1.71 mmol) and
3-bromo-5-(2-methoxyphenyl)pyridine (430 mg, 1.63 mmol)
(synthesized by Suzuki coupling according to general procedure B
from 3,5-dibromopyridine and 2-methoxyphenylboronic acid) after
flash chromatography (hexane/ethyl acetate, 1/4, R.sub.f=0.10) as a
colorless crystalline solid (106 mg, 0.29 mmol, 18%). .sup.1H-NMR
(500 MHz, CDCl.sub.3): .delta.=2.72 (t, .sup.3J=7.6 Hz, 2H), 3.04
(t, .sup.3J=7.6 Hz, 2H), 3.26 (t, .sup.3J=8.5 Hz, 2H), 3.84 (s,
3H), 4.13 (t, .sup.3J=8.5 Hz, 2H), 7.02 (d, .sup.3J=8.2 Hz, 1H),
7.07 (m, 1H), 7.25 (s, 1H), 7.32 (s, 1H), 7.35-7.40 (m, 2H), 7.95
(m, 1H), 8.71 (m. 2H).
Example 45
8-[5-(3,5-Difluorophenyl)pyridin-3-yl]-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]-
-quinolin-4-one
##STR00141##
[0375] The title compound was obtained according to general
procedure B from
8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2,5,6-tetrahydro--
pyrrolo[3,2,1-ij]quinolin-4-one (404 mg, 1.35 mmol) and
3-bromo-5-(3,5-difluorophenyl)pyridine (315 mg, 2.0 mmol)
(synthesized by Suzuki coupling according to general procedure B
from 3,5-dibromopyridine and 3,5-difluorophenylboronic acid) after
flash chromatography (hexane/ethyl acetate, 3/7, R.sub.f=0.10) as a
colorless crystalline solid (104 mg, 0.29 mmol, 21%). .sup.1H-NMR
(500 MHz, CDCl.sub.3): .delta.=2.73 (t, .sup.3J=7.6 Hz, 2H), 3.06
(t, .sup.3J=7.6 Hz, 2H), 3.27 (t, .sup.3J=8.5 Hz, 2H), 4.15 (t,
.sup.3J=8.5 Hz, 2H), 6.87 (m, 1H), 7.14 (m, 2H), 7.26 (s, 1H), 7.33
(s, 1H), 7.93 (m, 1H), 8.73 (d, .sup.4J=2.2 Hz, 1H), 8.80 (d,
.sup.4J=1.9 Hz, 1H).
[0376] According to Examples 36-45 using the general procedures A
or B and the appropriate starting compounds (see Schemes 1-19) also
the following compounds are synthesized:
##STR00142## ##STR00143## ##STR00144## ##STR00145##
Example 46
8-Fluoro-6-pyridin-3-yl-3,4,4a,8a-tetrahydro-1H-quinolin-2-one
##STR00146##
[0378] The title compound was obtained via Suzuki coupling
according to general procedure C from
6-Bromo-8-fluoro-3,4,4a,8a-tetrahydro-1H-quinolin-2-one (321 mg,
1.32 mmol) and 3-pyridineboronic acid (210 mg, 1.71 mmol) after
flash chromatography on silica gel (dichloromethane/methanol, 20/1,
R.sub.f=0.25) as white solid (274 mg, 1.13 mmol, 86%), mp
203.degree. C. .sup.1H-NMR (500 MHz, CDCl.sub.3): .delta.=2.72 (t,
.sup.3J=7.9 Hz, 2H), 3.09 (t, .sup.3J=7.9 Hz, 2H), 7.20 (s, 1H),
7.21 (d, .sup.3J.sub.H,F=11.0 Hz, 1H), 7.36 (dd, .sup.3J=4.8, 7.9
Hz, 1H), 7.76 (s, br, 1H), 7.81 (dt, .sup.3J=7.9 Hz, .sup.4J=2.3
Hz, 1H), 8.60 (dd, .sup.3J=4.8 Hz, .sup.4J=2.0 Hz, 1H), 8.80 (d,
.sup.4J=2.0 Hz, 1H). .sup.13C-NMR (125 MHz, CDCl.sub.3):
.delta.=25.5, 30.5, 120.8, 112.5, 112.6, 121.9, 122.0, 123.6,
134.0, 135.2, 147.9, 148.8, 149.0, 150.9, 169.8. MS m/z 243
(MH.sup.+).
Example 47
7-Fluoro-6-pyridin-3-yl-3,4,4a,8a-tetrahydro-1H-quinolin-2-one
##STR00147##
[0380] The title compound was obtained via Suzuki coupling
according to general procedure C from
6-Bromo-7-fluoro-3,4,4a,8a-tetrahydro-1H-quinolin-2-one (130 mg,
0.53 mmol) and 3-pyridineboronic acid (86 mg, 0.7 mmol) after flash
chromatography on silica gel (dichloromethane/methanol, 20/1,
R.sub.f=0.27) as white solid (107 mg, 0.44 mmol, 83%), mp
228.degree. C. .sup.1H-NMR (500 MHz, CDCl.sub.3): .delta.=2.70 (t,
.sup.3J=7.9 Hz, 2H), 3.02 (t, .sup.3J=7.9 Hz, 2H), 6.69 (d,
.sup.3J.sub.H,F=10.8 Hz, 1H), 7.23 (d, .sup.4J.sub.H,F=7.9 Hz, 1H),
7.36 (dd, .sup.3J=4.8, 7.9 Hz, 1H), 7.83 (dt, .sup.3J=7.9 Hz,
.sup.4J=2.3 Hz, 1H), 8.59 (dd, .sup.3J=4.8 Hz, .sup.4J=2.0 Hz, 1H),
8.76 (d, .sup.4J=2.0 Hz, 1H), 8.92 (s, 1H). .sup.13C-NMR (125 MHz,
CDCl.sub.3): .delta.=24.8, 30.6, 103.5, 103.7, 119.9, 123.3, 129.5,
131.2, 136.0, 138.6, 148.6, 149.4, 159.0, 171.6. MS m/z 243
(MH.sup.+).
Example 48
8-Fluoro-6-isoquinolin-4-yl-3-yl-3,4,4a,8a-tetrahydro-1H-quinolin-2-one
##STR00148##
[0382] The title compound was obtained via Suzuki coupling
according to general procedure C from
6-Bromo-8-fluoro-3,4,4a,8a-tetrahydro-1H-quinolin-2-one (169 mg,
0.69 mmol) and isoquinolin-4-yl boronic acid (144 mg, 0.83 mmol)
after flash chromatography on silica gel (dichloromethane/methanol,
20/1, R.sub.f=0.32) as white solid (172 mg, 0.59 mmol, 85%), mp
202.degree. C. .sup.1H-NMR (500 MHz, CDCl.sub.3): .delta.=2.75 (t,
.sup.3J=7.9 Hz, 2H), 3.11 (t, .sup.3J=7.9 Hz, 2H), 7.13 (s, 1H),
7.17 (d, .sup.3J.sub.H,F=10.7 Hz, 1H), 7.64-7.73 (m, 2H), 7.74 (s,
br, 1H), 7.90 (d, .sup.3J=8.2 Hz, 1H), 8.06 (d, .sup.3J=7.9 Hz,
1H), 8.45 (s, 1H), 9.27 (s, 1H). .sup.13C-NMR (125 MHz,
CDCl.sub.3): .delta.=25.5, 30.5, 124.3, 124.9, 125.4, 126.0, 127.4,
128.1, 128.4, 130.9, 131.6, 132.1, 134.0, 142.8, 149.5, 152.4. MS
m/z 293 (MH.sup.+).
Example 49
7-Fluoro-6-isoquinolin-4-yl-3-yl-3,4,4a,8a-tetrahydro-1H-quinolin-2-one
##STR00149##
[0384] The title compound was obtained via Suzuki coupling
according to general procedure C from
6-Bromo-7-fluoro-3,4,4a,8a-tetrahydro-1H-quinolin-2-one (169 mg,
0.69 mmol) and isoquinolin-4-yl boronic acid (144 mg, 0.83 mmol)
after flash chromatography on silica gel (dichloromethane/methanol,
20/1, R.sub.f=0.32) as white solid (160 mg, 0.55 mmol, 79%), mp
281.degree. C. .sup.1H-NMR (500 MHz, CDCl.sub.3): .delta.=2.73 (t,
.sup.3J=7.9 Hz, 2H), 3.03 (t, .sup.3J=7.9 Hz, 2H), 6.74 (d,
.sup.3J.sub.H,F=9.8 Hz, 1H), 7.23 (d, .sup.4J.sub.H,F=7.4 Hz, 1H),
7.62-7.70 (m, 3H), 8.05 (d, .sup.3J=8.0 Hz, 1H), 8.48 (s, 1H), 8.62
(s, 1H), 9.29 (s, 1H). .sup.13C-NMR (125 MHz, CDCl.sub.3):
.delta.=24.8, 30.7, 103.2, 117.5, 118.6, 119.7, 124.7, 127.1,
127.3, 127.9, 128.3, 130.7, 134.5, 143.6, 152.7, 159.4, 171.4. MS
m/z 293 (MH.sup.+).
Example 50
7-Hydroxy-6-pyridin-3-yl-3,4,4a,8a-tetrahydro-1H-quinolin-2-one
##STR00150##
[0386] The title compound was obtained via Suzuki coupling
according to general procedure C from
6-Bromo-7-hydroxy-3,4,4a,8a-tetrahydro-1H-quinolin-2-one (500 mg,
2.07 mmol) and 3-pyridineboronic acid (305 mg, 2.48 mmol) after
flash chromatography on silica gel (dichloromethane/methanol, 5/1,
R.sub.f=0.27) as white solid (72 mg, 0.30 mmol, 15%), mp
298.degree. C. .sup.1H-NMR (500 MHz, CDCl.sub.3): .delta.=2.44 (t,
.sup.3J=7.9 Hz, 2H), 2.81 (t, .sup.3J=7.9 Hz, 2H), 6.55 (s, 1H),
7.13 (s, 1H), 7.37 (dd, .sup.3J=4.8, 7.9 Hz, 1H), 7.89 (dt,
.sup.3J=7.9 Hz, .sup.4J=2.3 Hz, 1H), 8.42 (dd, .sup.3J=4.8 Hz,
.sup.4J=2.0 Hz, 1H), 8.70 (d, .sup.4J=2.0 Hz, 1H), 9.68 (s, 1H).
.sup.13C-NMR (125 MHz, CDCl.sub.3): .delta.=23.9, 30.7, 102.7,
114.6, 117.8, 122.9, 129.1, 133.9, 135.9, 138.9, 146.8, 149.3,
153.5, 170.2. MS m/z 241 (MH.sup.+).
Example 51
8-Fluoro-6-pyridin-3-yl-3,4,4a,8a-tetrahydro-1H-quinolin-2-thione
##STR00151##
[0388] The title compound was obtained according to general
procedure D from
8-Fluoro-6-pyridin-3-yl-3,4,4a,8a-tetrahydro-1H-quinolin-2-one (450
mg, 1.86 mmol) and Lawesson's reagent (451 mg, 1.11 mmol) after
flash chromatography on silica gel (dichloromethane/methanol, 10/1,
R.sub.f=0.22) as white solid (302 mg, 1.17 mmol, 63%), mp
235.degree. C. .sup.1H-NMR (500 MHz, CDCl.sub.3): .delta.=2.91 (t,
.sup.3J=7.9 Hz, 2H), 3.01 (t, .sup.3J=7.9 Hz, 2H), 7.48 (dd,
.sup.3J=4.8, 7.9 Hz, 1H), 7.53 (s, 1H), 7.59 (d,
.sup.3J.sub.H,F=11.0 Hz, 1H), 8.11 (dt, .sup.3J=7.9 Hz, .sup.4J=2.3
Hz, 1H), 8.57 (dd, .sup.3J=4.8 Hz, .sup.4J=2.0 Hz, 1H), 8.93 (d,
.sup.4J=2.0 Hz, 1H), 12.16 (s, 1H). .sup.13C-NMR (125 MHz,
CDCl.sub.3): .delta.=24.1, 30.5, 112.5, 121.9, 123.9, 129.6, 133.4,
133.5, 133.9, 147.3, 148.6, 149.6, 159.7, 200.7. MS m/z 259
(MH.sup.+).
Example 52
7-Fluoro-6-pyridin-3-yl-3,4,4a,8a-tetrahydro-1H-quinolin-2-thione
##STR00152##
[0390] The title compound was obtained according to general
procedure D from
7-Fluoro-6-pyridin-3-yl-3,4,4a,8a-tetrahydro-1H-quinolin-2-one (640
mg, 2.64 mmol) and Lawesson's reagent (641 mg, 1.59 mmol) after
flash chromatography on silica gel (dichloromethane/methanol, 10/1,
R.sub.f=0.22) as white solid (317 mg, 1.23 mmol, 66%), mp
248.degree. C. .sup.1H-NMR (500 MHz, CDCl.sub.3): .delta.=2.85 (t,
.sup.3J=7.9 Hz, 2H), 2.99 (t, .sup.3J=7.9 Hz, 2H), 7.03 (d,
.sup.3J.sub.H,F=11.0 Hz, 1H), 7.48-7.51 (m, 2H), 7.94 (dt,
.sup.3J=7.9 Hz, .sup.4J=2.3 Hz, 1H), 8.57 (dd, .sup.3J=4.8 Hz,
.sup.4J=2.0 Hz, 1H), 8.74 (d, .sup.4J=2.0 Hz, 1H), 12.33 (s, 1H).
.sup.13C-NMR (125 MHz, CDCl.sub.3): .delta.=23.1, 30.5, 103.6,
119.8, 119.9, 121.9, 123.6, 129.8, 130.6, 135.9, 137.7, 148.7,
157.9, 200.4. MS m/z 259 (MH.sup.+).
Example 53
7-(Pyridin-3-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one
##STR00153##
[0392] The title compound was obtained via Suzuki coupling
according to general procedure A from
7-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one (342 mg, 1.5 mmol) and
3-pyridineboronic acid (242 mg, 1.95 mmol) after flash
chromatography on silica gel (dichloromethane/methanol, 95/5,
R.sub.f=0.08) as pale yellow solid (121 mg, 0.53 mmol, 36%), mp
(dichloromethane/methanol) 256.degree. C. .sup.1H-NMR (500 MHz,
DMSO-d.sub.6): .delta.=4.62 (s, 2H), 7.00 (d, .sup.3J=8.2 Hz, 1H);
7.32-7.34 (m, 2H), 7.44 (ddd, .sup.3J=7.9 Hz, .sup.3J=4.7 Hz,
.sup.5J=0.8 Hz, 1H), 8.02 (m, 1H), 8.52 (dd, .sup.3J=4.7 Hz,
.sup.4J=1.6 Hz, 1H), 8.85 (d, .sup.4J=2.5 Hz, 1H), 10.82 (s, 1H).
.sup.13C-NMR (125 MHz, DMSO-d.sub.6): .delta.=66.7, 114.3, 116.3,
120.7, 123.7, 127.2, 131.9, 133.5, 134.6, 143.7, 147.2, 148.1,
164.6. MS m/z 227.7 (MH.sup.+).
Example 54
6-(Pyridin-3-yl)benzo[d]oxazol-2(3H)-one
##STR00154##
[0394] The title compound was obtained via Suzuki coupling
according to general procedure C from
6-bromobenzo[d]oxazol-2(3H)-one (428 mg, 2.0 mmol) and
3-pyridineboronic acid (320 mg, 2.6 mmol) with Cs.sub.2CO.sub.3 as
base instead of Na.sub.2CO.sub.3 after flash chromatography on
silica gel (dichloromethane/methanol, 95/5, R.sub.f=0.19) and flash
chromatography on silica gel (ethyl acetate, R.sub.f=0.27) as
colorless solid (99 mg, 0.47 mmol, 23%), mp (ethyl acetate)
265.degree. C. .sup.1H-NMR (500 MHz, DMSO-d.sub.6): .delta.=7.20
(d, .sup.3J=8.2 Hz, 1H), 7.46 (ddd, .sup.3J=7.9 Hz, .sup.3J=4.7 Hz,
.sup.5J=0.6 Hz, 1H), 7.51 (dd, .sup.3J=8.0 Hz, .sup.4J=1.7 Hz, 1H),
7.71 (d, .sup.4J=1.9 Hz, 1H), 8.06 (m, 1H), 8.54 (dd, .sup.3J=4.7
Hz, .sup.4J=1.6 Hz, 1H), 8.88 (d, .sup.4J=2.5 Hz, 1H), 11.73 (s,
1H). .sup.13C-NMR (125 MHz, DDMSO-d.sub.6): .delta.=108.0, 110.1,
122.5, 123.7, 130.4, 131.1, 133.8, 135.1, 144.0, 147.4, 148.1,
154.3.
Example 55
7-(Isoquinolin-4-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one
##STR00155##
[0396] The title compound was obtained via Suzuki coupling
according to general procedure A from
7-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one (242 mg, 1.95 mmol) and
4-isoquinolineboronic acid (337 mg, 1.95 mmol) after flash
chromatography on silica gel (dichloromethane/methanol, 97/3,
R.sub.f=0.13) as off-white solid (177 mg, 0.64 mmol, 43%), mp
(dichloromethane/methanol) 266.degree. C. .sup.1H-NMR (500 MHz,
DMSO-d.sub.6): .delta.=4.66 (s, 2H), 7.08 (d, .sup.3J=8.5 Hz, 1H),
7.12-7.13 (m, 2H), 7.73 (m, 1H), 7.80 (m, 1H), 7.89 (d, .sup.3J=8.5
Hz, 1H), 8.21 (d, .sup.3J=8.2 Hz, 1H), 8.41 (s, 1H), 9.32 (s, 1H),
10.88 (s, 1H). .sup.13C-NMR (125 MHz, DMSO-d.sub.6): .delta.=66.7,
115.9, 117.4, 123.9, 124.0, 127.1, 127.4, 127.9, 128.0, 131.0,
131.1, 131.7, 133.1, 142.3, 143.3, 151.7, 164.7. MS m/z 276.6
(MH.sup.+).
Example 56
6-(Isoquinolin-4-yl)-3,4-dihydroquinoxalin-2(1H)-one
##STR00156##
[0398] The title compound was obtained via Suzuki coupling
according to general procedure A from
6-bromo-3,4-dihydroquinoxalin-2(1H)-one (340 mg, 1.5 mmol) and
4-isoquinolineboronic acid (337 mg, 1.95 mmol) after flash
chromatography on silica gel (dichloromethane/methanol, 95/5,
R.sub.f=0.19) and crystallization from ethanol as yellow solid (148
mg, 0.54 mmol, 36%), mp (ethanol)>300.degree. C. .sup.1H-NMR
(500 MHz, DMSO-d.sub.6): .delta.=3.82 (d, .sup.4J=1.8 Hz, 2H), 6.14
(s, 1H), 6.75 (dd, .sup.3J=7.9 Hz, .sup.4J=1.6 Hz, 1H), 6.82 (d,
.sup.4J=1.8 Hz, 1H), 6.90 (d, .sup.3J=7.9 Hz, 1H), 7.71 (m, 1H),
7.78 (m, 1H), 7.93 (d, .sup.3J=8.5 Hz, 1H), 8.19 (d, .sup.3J=8.2
Hz, 1H), 8.37 (s, 1H), 9.28 (s, 1H), 10.42 (s, 1H). .sup.13C-NMR
(125 MHz, DMSO-d.sub.6): .delta.=46.1, 114.4, 115.0, 119.2, 124.2,
126.0, 127.3, 127.9, 127.9, 130.7, 130.7, 132.7, 133.2, 134.9,
142.0, 151.4, 165.9. MS m/z 276.0 (MH.sup.+).
Example 57
4-Methyl-6-(pyridin-3-yl)-3,4-dihydroquinoxalin-2(1H)-one
##STR00157##
[0400] The title compound was obtained via Suzuki coupling
according to general procedure A from
6-bromo-4-methyl-3,4-dihydroquinoxalin-2(1H)-one (342 mg, 1.42
mmol) and 3-pyridineboronic acid (229 mg, 1.86 mmol) after flash
chromatography on silica gel (dichloromethane/methanol, 97/3,
R.sub.f=0.09) and crystallization from acetone as pale yellow solid
(55 mg, 0.23 mmol, 16%), mp (acetone)>300.degree. C. .sup.1H-NMR
(500 MHz, DMSO-d.sub.5): .delta.=2.87 (s, 3H), 3.70 (s, 2H), 6.90
(d, .sup.3J=7.9 Hz, 1H), 6.98 (s, 1H), 7.06 (d, .sup.3J=7.9 Hz,
1H), 7.43 (dd, .sup.3J=7.6 Hz, .sup.3J=5.0 Hz, 1H), 8.02 (dd,
.sup.3J=7.6 Hz, .sup.4J=1.6 Hz, 1H), 8.51 (d, .sup.3J=4.7 Hz, 1H),
8.86 (d, .sup.4J=2.2 Hz, 1H), 10.52 (s, 1H). .sup.13C-NMR (125 MHz,
DMSO-d.sub.6): .delta.=36.8, 54.0, 109.7, 115.1, 117.0, 123.6,
127.4, 131.9, 133.6, 135.8, 136.7, 147.3, 147.7, 165.9. MS m/z
240.0 (MH.sup.+).
Example 58
6-(Pyridin-3-yl)-1H-benzo[d][1,3]oxazin-2(4H)-one
##STR00158##
[0402] The title compound was obtained via Suzuki coupling
according to general procedure C from
6-bromo-1H-benzo[d][1,3]oxazin-2(4H)-one (342 mg, 1.5 mmol) and
3-pyridineboronic acid (240 mg, 1.95 mmol) after flash
chromatography on silica gel (dichloromethane/methanol, 97/3,
R.sub.f=0.12) and crystallization from acetone as colorless solid
(85 mg, 0.38 mmol, 25%), mp (acetone) 211.degree. C. .sup.1H-NMR
(500 MHz, DMSO-d.sub.6): .delta.=5.35 (s, 2H), 7.00 (d, .sup.3J=8.2
Hz, 1H), 7.46 (dd, .sup.3J=8.2 Hz, .sup.3J=4.7 Hz, 1H), 7.61 (s,
1H), 7.64 (dd, .sup.3J=8.0 Hz, .sup.4J=2.0 Hz, 1H), 8.01 (m, 1H),
8.53 (dd, .sup.3J=4.7 Hz, .sup.4J=1.6 Hz, 1H), 8.85 (d, .sup.4J=1.9
Hz, 1H), 10.29 (s, 1H). .sup.13C-NMR (125 MHz, DMSO-d.sub.6):
.delta.=67.4, 114.2, 119.2, 122.9, 123.7, 125.1, 127.2, 131.0,
133.4, 136.4, 147.1, 148.0, 151.5.
Example 59
6-(Isoquinolin-4-yl)-1H-benzo[d][1,3]oxazin-2(4H)-one
##STR00159##
[0404] The title compound was obtained via Suzuki coupling
according to general procedure C from
6-bromo-1H-benzo[d][1,3]oxazin-2(4H)-one (255 mg, 1.12 mmol) and
4-isoquinolineboronic acid (232 mg, 1.34 mmol) after flash
chromatography on silica gel (dichloro-methane/methanol, 98/2,
R.sub.f=0.06) and crystallization from acetone as colorless solid
(74 mg, 0.27 mmol, 24%), mp (acetone) 215.degree. C. .sup.1H-NMR
(500 MHz, DMSO-d.sub.6): .delta.=5.38 (s, 2H), 7.08 (d, .sup.3J=8.2
Hz, 1H), 7.41 (s, 1H), 7.44 (dd, .sup.3J=8.2 Hz, .sup.4J=1.9 Hz,
1H), 7.73 (m, 1H), 7.79 (m, 1H), 7.88 (d, .sup.3J=8.5 Hz, 1H), 8.21
(d, .sup.3J=8.2 Hz, 1H), 8.41 (s, 1H), 9.32 (s, 1H), 10.34 (s, 1H).
.sup.13C-NMR (125 MHz, DMSO-d.sub.6): .delta.=67.39, 113.8, 118.9,
124.0, 125.9, 127.4, 127.9, 128.0, 130.2, 130.2, 131.0, 131.8,
133.1, 136.3, 142.3, 151.6, 151.7.
Example 60
8-(1-(1H-imidazol-1-yl)propyl)-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-
-4-one
##STR00160##
[0406] To a solution of
1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-one (1.73 g, 10.0
mmol) and AlCl.sub.3 (4.0 g, 30.0 mmol) in 80 ml dry
dichloromethane was added dropwise propionyl chloride (1.31 mL,
15.0 mmol) at room temperature. The mixture was refluxed overnight,
cooled to ambient temperature and quenched by addition of a cold
mixture of 10 ml concentrated hydrochloric acid and 20 ml water.
Extraction with dichloromethane (3.times.75 ml), followed by drying
over MgSO.sub.4 and removal of the solvent in vacuo gave the crude
product, which was purified by flash chromatography on silica gel
(hexanes/ethyl acetate, 3/7, R.sub.f=0.16) to yield a green solid
(1.20 g, 5.20 mmol). This was dissolved in 26 ml methanol and
sodium boron hydride (236 mg, 6.21 mmol) was added portionwise at
0.degree. C. After stirring for 1 h, water was added and the
mixture was extracted with ethyl acetate (3.times.75 ml). Drying
over MgSO.sub.4 and removal of the solvent gave the alcohol as
crude product. A solution of the obtained alcohol in 10 ml dry THF
was added to a solution of thionylbis(imidazole) (prepared
previously by reaction of imidazole (1.47 g, 21.6 mmol) with
thionyl chloride (0.39 mL, 5.4 mmol) in 20 mL THF and filtration to
remove precipitated imidazole hydrochloride) at 0.degree. C. The
reaction mixture was stirred for one hour at 0.degree. C. and an
additional 18 h at ambient temperature. Water was added and the
mixture extracted with ethyl acetate (3.times.75 ml), the combined
organic extracts washed with water and brine, and the solvent was
removed in vacuo after drying over MgSO.sub.4. The crude product
was purified by flash chromatography on silica gel (ethyl
acetate/methanol, 9/1, R.sub.f=0.1) to yield
8-(1-(1H-imidazol-1-yl)propyl)-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinoli-
n-4-one (200 mg, 0.71 mmol, 7%) as a white solid, mp (ethyl
acetate/methanol) 195.degree. C. .sup.1H-NMR (500 MHz, CDCl.sub.3):
.delta.=0.93 (t, .sup.3J=7.2, 3H), 2.13-2.25 (m, 2H), 2.65 (t,
.sup.3J=7.9, 2H), 2.93 (t, .sup.3J=7.9, 2H), 3.14 (t, .sup.3J=8.5,
2H), 4.06 (t, .sup.3J=8.5, 2H), 4.90-4.94 (t, .sup.3J=7.6, 1H),
6.82 (s, 1H), 6.90 (s, 1H), 6.92 (s, 1H), 7.06 (s, 1H), 7.59 (s,
1H). .sup.13C-NMR (125 MHz, CDCl.sub.3): .delta.=11.4, 24.6, 27.9,
29.0, 31.7, 45.6, 63.6, 117.8, 120.6, 121.9, 124.3, 129.6, 129.8,
135.8, 136.4, 141.7, 167.7. MS m/z 282.07 (MH.sup.+).
Example 61
8-((1H-imidazol-1-yl)(phenyl)methyl)-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]qu-
inolin-4-one
##STR00161##
[0408] To a solution of
1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-one (1.94 g, 10.8
mmol) and AlCl.sub.3 (3.99 g, 29.9 mmol) in 50 ml dry
dichloromethane was added dropwise benzoyl chloride (3.14 g, 22.3
mmol) at 0.degree. C. The mixture was then refluxed overnight,
cooled to ambient temperature and quenched by, addition of a cold
mixture of 10 ml concentrated hydrochloric acid and 20 ml water.
Extraction with ethyl acetate (3.times.100 ml), followed by drying
over MgSO.sub.4 and removal of the solvent in vacuo gave the crude
product, which was purified by flash chromatography on silica gel
(hexanes/ethyl acetate, 1/1, R.sub.f=0.14) to yield yellow crystals
(1.82 g, 6.57 mmol). These were dissolved in 50 ml methanol and
sodium boron hydride (378 mg, 10.0 mmol) was added portionwise at
0.degree. C. After stirring for 1 h, water was added and the
mixture was extracted with ethyl acetate (3.times.100 ml). Drying
over MgSO.sub.4 and removal of the solvent gave the alcohol as
crude product. A solution of the obtained alcohol in 10 ml dry THF
was added to a solution of thionylbis(imidazol e) (prepared
previously by reaction of imidazole (2.72 g, 40.0 mmol) with
thionyl chloride (0.73 mL, 10.0 mmol) in 30 mL THF and filtration
to remove precipitated imidazole hydrochloride) at 0.degree. C. The
reaction mixture was stirred for one hour at 0.degree. C. and an
additional 18 h at ambient temperature. Water was added and the
mixture extracted with ethyl acetate (3.times.100 ml), the combined
organic extracts washed with water and brine, and the solvent was
removed in vacuo after drying over MgSO.sub.4. The crude product
was purified by two subsequent crystallizations from acetone to
yield
8-((1H-imidazol-1-yl)(phenyl)methyl)-1,2,5,6-tetrahydropyrrolo[3,2,-
1-ij]quinolin-4-one (385 mg, 1.17 mmol, 11%) as colorless needles,
mp (acetone) 186.degree. C. .sup.1H-NMR (500 MHz, CDCl.sub.3):
.delta.=2.67 (t, .sup.3J=7.7 Hz, 2H), 2.92 (t, .sup.3J=7.7 Hz, 2H),
3.14 (t, .sup.3J=8.5 Hz, 2H), 4.09 (t, .sup.3J=8.5 Hz, 2H), 6.45
(s, 1H), 6.75 (s, 1H), 6.81 (s, 1H), 6.85 (s, 1H), 7.09 (m, 3H),
7.33-7.39 (m, 3H), 7.41 (s, 1H). .sup.13C-NMR (125 MHz,
CDCl.sub.3): .delta.=22.3, 24.4, 27.7, 31.5, 45.4, 56.6, 117.9,
120.4, 121.2, 123.5, 129.3, 129.6, 135.9, 136.9, 141.4, 167.5.
Example 62
8-((4-Fluorophenyl)(1H-imidazol-1-yl)methyl)-1,2,5,6-tetrahydropyrrolo-[3,-
2,1-ij]quinolin-4-one
##STR00162##
[0410] The title compound was obtained according to general
procedure E from
8-(tributylstannyl)-1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-o-
ne (1.33 g, 2.86 mmol) and 4-fluorobenzoyl chloride (0.68 mL, 5.72
mmol) after flash chromatography on silica gel
(methanol/dichloromethane, 1/50, R.sub.f=0.08) as a pale yellow
solid (300 mg, 0.86 mmol, 30%). mp (methanol/dichloromethane)
203.degree. C. .sup.1H-NMR (500 MHz, CDCl.sub.3): .delta.=2.67 (t,
.sup.3J=7.8 Hz, 2H), 2.92 (t, .sup.3J=7.8 Hz, 2H), 3.15 (t,
.sup.3J=8.5 Hz, 2H), 4.09 (t, .sup.3J=8.5 Hz, 2H), 6.46 (s, 1H),
6.73 (s, 1H), 6.78 (s, 1H), 6.85 (s, 1H), 7.06 (s, 2H), 7.07 (s,
2H), 7.13 (s, 1H), 7.47 (s, 1H). .sup.13C-NMR (125 MHz,
CDCl.sub.3): .delta.=24.4, 27.7, 31.4, 45.4, 64.5, 116.0 (d,
.sup.3J.sub.C,F=21.8 Hz), 119.3, 120.5, 123.1, 125.5, 128.9, 129.6
(d, .sup.3J.sub.C,F=8.2 Hz), 129.8, 133.9, 135.0 (d,
.sup.4J.sub.C,F=3.5 Hz), 137.0, 141.9, 162.5 (d,
.sup.1J.sub.C,F=248 Hz), 167.5. MS m/z 280.60
(M.sup.+-imidazole).
Example 63
8-((1H-imidazol-1-yl)(4-methoxyphenyl)methyl)-1,2,5,6-tetrahydropyrrolo-[3-
,2,1-ij]quinolin-4-one
##STR00163##
[0412] The title compound was obtained according to general
procedure E from
8-(tributylstannyl)-1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-o-
ne (2.0 g, 4.33 mmol) and 4-methoxybenzoyl chloride (1.17 mL, 8.66
mmol) after flash chromatography on silica gel
(methanol/dichloromethane, 1/50, R.sub.f=0.05) as a colorless
crystal (90 mg, 0.25 mmol, 6%). mp (methanol/dichloromethane)
55.degree. C. .sup.1H-NMR (500 MHz, CDCl.sub.3): .delta.=2.66 (t,
.sup.3J=7.8 Hz, 2H), 2.91 (t, .sup.3J=7.8 Hz, 2H), 3.14 (t,
.sup.3J=8.5 Hz, 2H), 3.81 (s, 3H), 4.08 (t, .sup.3J=8.5 Hz, 2H),
6.40 (s, 1H), 6.72 (s, 1H), 6.78 (s, 1H), 6.86 (m, 1H), 6.88 (m,
2H), 7.02 (m, 2H), 7.11 (s, 1H), 7.43 (s, 1H). .sup.13C-NMR (125
MHz, CDCl.sub.3): .delta.=24.4, 27.7, 31.4, 45.4, 55.3, 64.6,
114.3, 120.4, 123.0, 125.3, 129.2, 129.6, 131.1, 134.7, 141.6,
159.6, 167.5. MS m/z 292.60 (M.sup.+-imidazole).
Example 64
8-(1-(1H-imidazol-1-yl)-2-methylpropyl)-1,2,5,6-tetrahydropyrrolo[3,2,1-ij-
]-quinolin-4-one
##STR00164##
[0414] The title compound was obtained according to general
procedure E from
8-(tributylstannyl)-1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-o-
ne (1.5 g, 3.24 mmol) and isobutyryl chloride (0.68 mL, 6.49 mmol)
after flash chromatography on silica gel (methanol/dichloromethane,
1/50, R.sub.f=0.1) as a pale yellow solid (35 mg, 0.12 mmol, 4%).
mp (methanol/dichloromethane) 151.degree. C. .sup.1H-NMR (500 MHz,
CDCl.sub.3): .delta.=0.91 (t, .sup.3J=6.9 Hz, 6H), 2.54 (m, 1H),
2.66 (t, .sup.3J=7.8 Hz, 2H), 2.94 (t, .sup.3J=7.8 Hz, 2H), 3.16
(t, .sup.3J=8.5 Hz, 2H), 4.07 (t, .sup.3J=8.5 Hz, 2H), 4.55 (d,
.sup.3J=10.5 Hz, 1H), 6.92 (s, 1H), 6.99 (s, 1H), 7.01 (s, 2H),
7.06 (s, 1H), 7.68 (s, 1H). .sup.13C-NMR (125 MHz, CDCl.sub.3):
.delta.=20.1, 20.5, 24.4, 27.7, 31.4, 32.5, 45.4, 69.5, 117.4,
120.4, 122.3, 124.7, 128.9, 129.6, 134.6, 136.1, 141.5, 167.5. MS
m/z 228.60 (M.sup.+-imidazole).
Example 65
8-((3-Fluorophenyl)(1H-imidazol-1-yl)methyl)-1,2,5,6-tetrahydropyrrolo-[3,-
2,1-ij]quinolin-4-one
##STR00165##
[0416] The title compound was obtained according to general
procedure E from
8-(tributylstannyl)-1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-o-
ne (1.5 g, 3.24 mmol) and 3-fluorobenzoyl chloride (0.79 mL, 6.48
mmol) after flash chromatography on silica gel
(methanol/dichloromethane, 1/50, R.sub.f=0.07) as a pale yellow
solid (159 mg, 0.46 mmol, 14%) mp (methanol/dichloromethane)
195.degree. C. .sup.1H-NMR (500 MHz, CDCl.sub.3): .delta.=2.68 (t,
.sup.3J=7.8 Hz, 2H), 2.92 (t, .sup.3J=7.8 Hz, 2H), 3.15 (t,
.sup.3J=8.5 Hz, 2H), 4.09 (t, .sup.3J=8.5 Hz, 2H), 6.43 (s, 1H),
6.75 (s, 1H), 6.78 (m, 1H), 6.81 (s, 1H), 6.84 (s, 1H), 6.88 (m,
1H), 7.04 (m, 1H), 7.11 (s, 1H), 7.34 (m, 1H), 7.41 (s, 1H).
.sup.13C-NMR (125 MHz, CDCl.sub.3): .delta.=24.4, 27.7, 31.4, 45.4,
64.4, 114.9 (d, .sup.2J.sub.C,F=22.8 Hz), 115.4 (d,
.sup.2J.sub.C,F=21.1 Hz), 120.5, 123.3, 123.4, 123.4, 125.7, 129.7,
129.7, 130.5 (d, .sup.3J.sub.C,F=8.2 Hz), 133.6, 141.9, 142.0,
142.0, 163.0 (d, .sup.1J.sub.C,F=248 Hz), 167.5. MS m/z 280.60
(M.sup.+-imidazole).
Example 66
8-((2-Fluorophenyl)(1H-imidazol-1-yl)methyl)-1,2,5,6-tetrahydropyrrolo-[3,-
2,1-ij]quinolin-4-one
##STR00166##
[0418] The title compound was obtained according to general
procedure E from
8-(tributylstannyl)-1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-o-
ne (1.2 g, 2.60 mmol) and 2-fluorobenzoyl chloride (0.63 mL, 5.20
mmol) after flash chromatography on silica gel
(methanol/dichloromethane, 1/50, R.sub.f=0.06) as a pale yellow
solid (105 mg, 0.30 mmol, 12%). mp (methanol/dichloromethane)
176.degree. C. .sup.1H-NMR (500 MHz, CDCl.sub.3): .delta.=2.67 (t,
.sup.3J=7.8 Hz, 2H), 2.91 (t, .sup.3J=7.8 Hz, 2H), 3.14 (t,
.sup.3J=8.5 Hz, 2H), 4.08 (t, .sup.3J=8.5 Hz, 2H), 6.73 (s, 1H),
6.74 (s, 1H), 6.80 (s, 1H), 6.85 (s, 1H), 6.88 (m, 1H), 7.08-7.16
(m, 3H), 7.35 (m, 1H), 7.41 (s, 1H). .sup.13C-NMR (125 MHz,
CDCl.sub.3): .delta.=24.3, 27.6, 31.4, 45.4, 58.5 (d,
.sup.3J.sub.C,F=4.0 Hz), 115.8 (d, .sup.2J.sub.C,F=21.2 Hz), 119.3,
120.0, 123.0, 124.6 (d, .sup.4J.sub.C,F=3.5 Hz), 125.4, 127.0 (d,
.sup.3J.sub.C,F=13.1 Hz), 128.7 (d, .sup.4J.sub.C,F=2.9 Hz), 129.5,
129.6, 130.3 (d, .sup.3J.sub.C,F=8.3 Hz), 133.0, 137.3, 141.8,
160.0 (d, .sup.1J.sub.C,F=249 Hz), 167.5. MS m/z 280.00
(M.sup.+-imidazole).
Example 67
4-((2,4,5,6-Tetrahydro-4-oxo-1H-pyrrolo[3,2,1-ij]quinolin-8-yl)(1H-imidazo-
l-1-yl)methyl)benzonitrile
##STR00167##
[0420] The title compound was obtained according to general
procedure E from
8-(tributylstannyl)-1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-o-
ne (1.5 g, 3.24 mmol) and 4-cyanobenzoyl chloride (1.07 g, 6.48
mmol) after flash chromatography on silica gel
(methanol/dichloromethane, 1/50, R.sub.f=0.08) as a white solid
(302 mg, 0.85 mmol, 26%). mp (methanol/dichloromethane) 115.degree.
C. .sup.1H-NMR (500 MHz, CDCl.sub.3): .delta.=2.67 (t, .sup.3J=7.8
Hz, 2H), 2.92 (t, .sup.3J=7.8 Hz, 2H), 3.15 (t, .sup.3J=8.5 Hz,
2H), 4.09 (t, .sup.3J=8.5 Hz, 2H), 6.49 (s, 1H), 6.74 (s, 1H), 6.79
(s, 1H), 6.82 (s, 1H), 7.13 (s, 1H), 7.16 (d, .sup.3J=8.3 Hz, 2H),
7.40 (s, 1H), 7.66 (d, .sup.3J=8.3 Hz, 2H). .sup.13C-NMR (125 MHz,
CDCl.sub.3): .delta.=24.3, 27.6, 31.3, 45.4, 64.5, 112.4, 118.1,
119.0, 120.7, 123.5, 126.0, 128.2, 130.0, 130.0, 132.6, 132.7,
137.1, 142.2, 144.8, 167.4. MS m/z 355.62 (MH.sup.+).
Example 68
8-(Cyclopropyl(1H-imidazol-1-yl)methyl)-1,2,5,6-tetrahydropyrrolo[3,2,1-ij-
]quinolin-4-one
##STR00168##
[0422] The title compound was obtained according to general
procedure E from
8-(tributylstannyl)-1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-o-
ne (1.5 g, 3.24 mmol) and cyclopropanecarbonyl chloride (0.59 mL,
6.49 mmol) after flash chromatography on silica gel
(methanol/dichloromethane, 1/50, R.sub.f=0.09) as a white solid
(502 mg, 1.71 mmol, 53%). mp (methanol/dichloromethane) 147.degree.
C. .sup.1H-NMR (500 MHz, CDCl.sub.3): .delta.=0.42-0.50 (m, 2H),
0.76-0.85 (m, 2H), 1.46-1.54 (m, 1H), 2.66 (t, .sup.3J=7.8 Hz, 2H),
2.93 (t, .sup.3J=7.8 Hz, 2H), 3.15 (t, .sup.3J=8.5 Hz, 2H), 4.08
(t, .sup.3J=8.5 Hz, 2H), 4.30 (d, .sup.3J=9.3 Hz, 1H), 6.82 (s,
1H), 6.90 (s, 1H), 6.95 (s, 2H), 7.07 (s, 1H), 7.67 (s, 1H).
.sup.13C-NMR (125 MHz, CDCl.sub.3): .delta.=4.8, 5.3, 16.6, 24.4,
27.7, 31.5, 32.5, 45.4, 66.3, 118.3, 120.3, 121.8, 124.1, 129.3,
129.4, 135.6, 136.4, 141.4, 167.5. MS m/z 226.48
(M.sup.+-imidazole).
Example 69
8-((1H-imidazol-1-yl)(3-methoxyphenyl)methyl)-1,2,5,6-tetrahydropyrrolo-[3-
,2,1-ij]quinolin-4-one
##STR00169##
[0424] The title compound was obtained according to general
procedure E from
8-(tributylstannyl)-1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-o-
ne (1.5 g, 3.24 mmol) and 3-methoxybenzoyl chloride (0.98 mL, 6.48
mmol) after flash chromatography on silica gel
(methanol/dichloromethane, 1/50, R.sub.f=0.05) as a colorless
crystal (402 mg, 1.12 mmol, 35%). mp (methanol/dichloromethane)
66.degree. C. .sup.1H-NMR (500 MHz, CDCl.sub.3): .delta.=2.66 (t,
.sup.3J=7.8 Hz, 2H), 2.91 (t, .sup.3J=7.8 Hz, 2H), 3.13 (t,
.sup.3J=8.5 Hz, 2H), 3.76 (s, 3H), 4.08 (t, .sup.3J=8.5 Hz, 2H),
6.40 (s, 1H), 6.61 (t, .sup.4J=2.0 Hz, 1H), 6.67 (d, .sup.3J=7.6
Hz, 1H), 6.75 (s, 1H), 6.81 (s, 1H), 6.84 (m, 1H), 6.87 (dd,
.sup.3J=8.2 Hz, .sup.4J=2.5 Hz, 1H), 7.08 (m, 1H), 7.27 (t,
.sup.3J=7.8 Hz, 1H), 7.40 (s, 1H). .sup.13C-NMR (125 MHz,
CDCl.sub.3): .delta.=24.3, 27.6, 31.4, 45.4, 55.3, 64.8, 113.2,
114.0, 119.3, 120.1, 120.3, 123.2, 125.6, 129.4, 129.5, 129.9,
134.2, 137.3, 140.9, 141.6, 160.0, 167.5. MS m/z 360.60
(MH.sup.+).
Example 70
8-(Cyclobutyl(1H-imidazol-1-yl)methyl)-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]-
-quinolin-4-one
##STR00170##
[0426] The title compound was obtained according to general
procedure E from
8-(tributylstannyl)-1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-o-
ne (1.2 g, 2.60 mmol) and cyclobutanecarbonyl chloride (0.42 mL,
5.20 mmol) after flash chromatography on silica gel
(methanol/dichloromethane, 1/50, R.sub.f=0.09) as a white solid
(401 mg, 1.30 mmol, 50%). mp (methanol/dichloromethane) 121.degree.
C. .sup.1H-NMR (500 MHz, CDCl.sub.3): .delta.=1.76-1.99 (m, 4H),
2.01-2.07 (m, 1H), 2.14-2.21 (m, 1H), 2.65 (t, .sup.3J=7.8 Hz, 2H),
2.92 (t, .sup.3J=7.8 Hz, 2H), 3.08 (m, 1H), 3.13 (t, .sup.3J=8.5
Hz, 2H), 4.06 (t, .sup.3J=8.5 Hz, 2H), 4.93 (d, .sup.3J=10.4 Hz,
1H), 6.80 (s, 1H), 6.85 (s, 1H), 6.87 (s, 1H), 7.03 (s, 1H), 7.51
(s, 1H). .sup.13C-NMR (125 MHz, CDCl.sub.3): .delta.=17.5, 24.5,
26.3, 26.9, 27.8, 31.5, 39.8, 45.4, 67.3, 117.8, 120.3, 122.3,
124.4, 129.4, 129.5, 134.4, 136.2, 141.7, 167.3. MS m/z 240.10
(M.sup.+-imidazole).
Example 71
8-(Furan-2-yl(1H-imidazol-1-yl)methyl)-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]-
quinolin-4-one
##STR00171##
[0428] The title compound was obtained according to general
procedure E from
8-(tributylstannyl)-1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-o-
ne (1.2 g, 2.60 mmol) and furan-2-carbonyl chloride (0.51 mL, 5.20
mmol) after flash chromatography on silica gel
(methanol/dichloromethane, 3/100, R.sub.f=0.05) as a yellow solid
(112 mg, 0.35 mmol, 13%). mp (methanol/dichloromethane) 152.degree.
C. .sup.1H-NMR (500 MHz, CDCl.sub.3): .delta.=2.67 (t, .sup.3J=7.8
Hz, 2H), 2.92 (t, .sup.3J=7.8 Hz, 2H), 3.15 (t, .sup.3J=8.5 Hz,
2H), 4.08 (t, .sup.3J=8.5 Hz, 2H), 6.17 (d, .sup.4J=3.3 Hz, 1H),
6.38 (m, 2H), 6.78 (s, 1H), 6.84 (s, 1H), 6.89 (s, 1H), 7.08 (s,
1H), 7.45 (s, 2H). .sup.13C-NMR (125 MHz, CDCl.sub.3):
.delta.=24.3, 27.6, 31.4, 45.4, 58.8, 110.2, 110.5, 118.7, 120.4,
122.3, 124.7, 129.4, 129.6, 132.6, 136.8, 141.8, 143.4, 151.4,
167.5. MS m/z 252.50 (M.sup.+-imidazole).
Example 72
8-((1H-imidazol-1-yl)(thiophen-2-yl)methyl)-1,2,5,6-tetrahydropyrrolo[3,2,-
1-ij]quinolin-4-one
##STR00172##
[0430] The title compound was obtained according to general
procedure E from
8-(tributylstannyl)-1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-o-
ne (1.2 g, 2.60 mmol) and thiophene-2-carbonyl chloride (0.56 mL,
5.20 mmol) after flash chromatography on silica gel
(methanol/dichloromethane, 1/50, R.sub.f=0.09) as a white solid
(300 mg, 0.89 mmol, 34%). mp (methanol/dichloromethane) 170.degree.
C. .sup.1H-NMR (500 MHz, CDCl.sub.3): .delta.=2.67 (t, .sup.3J=7.8
Hz, 2H), 2.92 (t, .sup.3J=7.8 Hz, 2H), 3.15 (t, .sup.3J=8.5 Hz,
2H), 4.08 (t, .sup.3J=8.5 Hz, 2H), 6.61 (s, 1H), 6.82 (s, 1H), 6.86
(dt, .sup.3J=3.5 Hz, .sup.4J=1.0 Hz, 1H), 6.88 (s, 1H), 6.91 (m,
1H), 7.00 (dd, .sup.3J=5.1 Hz, .sup.3J=3.6 Hz, 1H), 7.09 (s, 1H),
7.34 (dd, .sup.3J=5.1 Hz, .sup.4J=1.2 Hz, 1H), 7.48 (s, 1H).
.sup.13C-NMR (125 MHz, CDCl.sub.3): .delta.=24.3, 27.7, 31.4, 45.4,
60.5, 118.9, 120.4, 122.3, 124.7, 126.7, 127.0, 127.5, 129.5,
129.6, 134.8, 136.9, 141.8, 142.5, 167.5. MS m/z 268.46
(M.sup.+-imidazole).
Example 73
3-((2,4,5,6-Tetrahydro-4-oxo-1H-pyrrolo[3,2,1-ij]quinolin-8-yl)(1H-imidazo-
l-1-yl)methyl)benzonitrile
##STR00173##
[0432] The title compound was obtained according to general
procedure E from
8-(tributylstannyl)-1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-o-
ne (1.2 g, 2.60 mmol) and 3-cyanobenzoyl chloride (861 mg, 5.20
mmol) after flash chromatography on silica gel
(methanol/dichloromethane, 1/50, R.sub.f=0.05) as a white solid (62
mg, 0.18 mmol, 7%). mp (methanol/dichloromethane) 202.degree. C.
.sup.1H-NMR (500 MHz, CDCl.sub.3): .delta.=2.68 (t, .sup.3J=7.8 Hz,
2H), 2.93 (t, .sup.3J=7.8 Hz, 2H), 3.16 (t, .sup.3J=8.5 Hz, 2H),
4.10 (t, .sup.3J=8.5 Hz, 2H), 6.48 (s, 1H), 6.73 (s, 1H), 6.78 (s,
1H), 6.83 (s, 1H), 7.14 (s, 1H), 7.30 (d, .sup.3J=7.9 Hz, 1H), 7.34
(s, 1H), 7.42 (s, 1H), 7.50 (t, .sup.3J=8.0 Hz, 1H), 7.64 (d,
.sup.3J=7.7 Hz, 1H). .sup.13C-NMR (125 MHz, CDCl.sub.3):
.delta.=24.3, 27.6, 31.3, 45.4, 64.2, 113.2, 118.1, 120.7, 123.4,
125.7, 129.8, 130.0, 131.1, 131.9, 132.0, 132.7, 141.2, 142.2,
167.5. MS m/z 287.20 (M.sup.+-imidazole).
Example 74
8-(1,1-Di(1H-imidazol-1-yl)ethyl)-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quino-
lin-4-one
##STR00174##
[0434] To a solution of imidazole (2.28 g, 33.4 mmol) in
dichloromethane (15 mL) was added SOCl.sub.2 (0.40 mL, 5.6 mmol)
under an atmosphere of nitrogen at 0.degree. C. The mixture was
stirred for 30 min, then
8-acetyl-1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-4-one (1.00 g,
4.60 mmol) was added. The mixture was stirred at ambient
temperature for 96 h, then neutralized with aqueous NaHCO.sub.3 and
extracted with CHCl.sub.3 (3.times.15 mL). The extracts were washed
with water and brine, dried over MgSO.sub.4 and concentrated in
vacuo. The residue was purified by flash chromatograph on silica
gel (methanol/dichloromethane, 1/20, R.sub.f=0.05) to yield a pale
yellow solid (330 mg, 0.99 mmol, 22%). mp
(methanol/dichloromethane) 189.degree. C. .sup.1H-NMR (500 MHz,
CDCl.sub.3): .delta.=2.53 (s, 3H), 2.67 (t, .sup.3J=7.8 Hz, 2H),
2.91 (t, .sup.3J=7.8 Hz, 2H), 3.14 (t, .sup.3J=8.5 Hz, 2H), 4.10
(t, .sup.3J=8.5 Hz, 2H), 6.52 (s, 1H), 6.56 (s, 1H), 6.82 (s, 2H),
7.13 (s, 2H), 7.35 (s, 2H). .sup.13C-NMR (125 MHz, CDCl.sub.3):
.delta.=24.4, 27.6, 30.3, 31.3, 45.5, 75.9, 118.0, 120.4, 121.2,
123.5, 129.8, 130.3, 135.6, 136.2, 142.8, 167.4.
Example 75
1,2,5,6-Tetrahydro-8-(hydroxy(pyridin-4-yl)methyl)pyrrolo[3,2,1-ij]quinoli-
n-4-one
##STR00175##
[0436] To a solution of
8-(pyridine-4-carbonyl)-1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-on-
e (200 mg, 0.72 mmol) in methanol (8 mL) was added sodium boron
hydride (27 mg, 0.72 mmol) at 0.degree. C. The mixture was stirred
at ambient temperature for 1 h before evaporation under reduced
pressure. The resulting solid was washed with water and diethyl
ether to yield a white solid (190 mg, 0.68 mmol, 94%). mp (diethyl
ether) 252.degree. C. .sup.1H-NMR (500 MHz, DMSO-d.sub.6):
.delta.=2.67 (t, .sup.3J=7.7 Hz, 2H), 2.87 (t, .sup.3J=7.7 Hz, 2H),
3.08 (t, .sup.3J=8.5 Hz, 2H), 3.90 (t, .sup.3J=8.5 Hz, 2H), 5.63
(t, .sup.3J=4.0 Hz, 1H), 6.00 (t, .sup.3J=4.0 Hz, 1H), 7.02 (s,
1H), 7.08 (s, 1H), 7.36 (dd, .sup.3J=4.5 Hz, .sup.4J=1.6 Hz, 2H),
8.46 (dd, .sup.3J=4.5 Hz, .sup.4J=1.6 Hz, 2H). .sup.13C-NMR (125
MHz, DMSO-d.sub.6): .delta.=23.7, 27.0, 31.0, 44.9, 73.0, 119.6,
121.0, 121.2, 123.4, 128.7, 139.3, 140.3, 149.3, 154.3, 166.5.
Example 76
1,2,5,6-Tetrahydro-8-((pyridin-4-yl)methyl)pyrrolo[3,2,1-ij]quinolin-4-one
##STR00176##
[0438] To a suspension of
1,2,5,6-tetrahydro-8-(hydroxy(pyridin-4-yl)methyl)pyrrolo[3,2,1-ij]quinol-
in-4-one (125 mg, 0.45 mmol) in dry dichloromethane (5 mL) was
added by syringe trifluoroacetic acid (0.34 mL, 4.46 mmol),
triethylsilane (0.22 mL, 1.34 mmol) and trifluoromethanesulfuric
acid (0.05 equivalent) under an atmosphere of nitrogen at 0.degree.
C. The resulting solution was stirred at ambient temperature for 48
h, before it was washed with aqueous NaHCO.sub.3 and water, dried
over MgSO.sub.4 and concentrated in vacuo. The residue was purified
by flash chromatography on silica gel (methanol/dichloromethane,
1/50, R.sub.f=0.1) to yield a pale yellow solid (65 mg, 0.25 mmol,
55%). mp (methanol/dichloromethane) 199.degree. C. .sup.1H-NMR (500
MHz, CDCl.sub.3): .delta.=2.66 (t, .sup.3J=7.7 Hz, 2H), 2.93 (t,
.sup.3J=7.7 Hz, 2H), 3.15 (t, .sup.3J=8.5 Hz, 2H), 3.89 (s, 2H)
4.07 (t, .sup.3J=8.5 Hz, 2H), 6.80 (s, 1H), 6.88 (s, 1H), 7.09 (dd,
.sup.3J=4.5 Hz, .sup.4J=1.4 Hz, 2H), 8.50 (dd, .sup.3J=4.5 Hz,
.sup.4J=1.4 Hz, 2H). .sup.13C-NMR (125 MHz, CDCl.sub.3):
.delta.=24.4, 27.7, 31.5, 41.0, 45.3, 120.3, 123.9, 124.0, 126.1,
129.4, 134.2, 140.1, 149.9, 150.2, 167.4.
Example 77
1,2,5,6-Tetrahydro-8-(hydroxy(phenyl)(pyridin-4-yl)methyl)pyrrolo[3,2,1-ij-
]-quinolin-4-one
##STR00177##
[0440] To a solution of
8-(pyridine-4-carbonyl)-1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-on-
e (200 mg, 0.72 mmol) in dry THF (5 mL) was added dropwise a
solution of PhMgBr (2.16 mL, 1 M in THF, 2.16 mmol) under an
atmosphere of nitrogen at -78.degree. C. Then the mixture was
stirred at the same temperature for 1 h, before it was warmed to
ambient temperature. After being stirred for 15 h, the reaction was
quenched with saturated aqueous NH.sub.4Cl (5 mL), extracted with
ethyl acetate (3.times.10 mL), dried over MgSO.sub.4 and
concentrated in vacuo. The residue was purified by flash
chromatography on silica gel (methanol/dichloromethane, 1/30,
R.sub.f=0.1) to yield a pale yellow solid (120 mg, 0.34 mmol, 47%).
mp (methanol/dichloromethane) 195.degree. C. .sup.1H-NMR (500 MHz,
CDCl.sub.3): .delta.=2.63 (t, .sup.3J=7.7 Hz, 2H), 2.88 (t,
.sup.3J=7.7 Hz, 2H), 3.11 (t, .sup.3J=8.3 Hz, 2H), 3.53 (s, 1H),
4.04 (t, .sup.3J=8.3 Hz, 2H), 6.88 (s, 1H), 6.93 (s, 1H), 7.25-7.33
(m, 7H), 8.49 (d, .sup.3J=3.2 Hz, 2H). .sup.13C-NMR (125 MHz,
CDCl.sub.3): .delta.=24.4, 27.7, 31.5, 45.4, 81.2, 119.5, 122.6,
123.1, 125.3, 127.7, 127.8, 128.2, 128.7, 140.9, 141.4, 145.7,
149.4, 155.6, 167.6.
Example 78
1,2,5,6-Tetrahydro-8-(phenyl(pyridin-4-yl)methyl)pyrrolo[3,2,1-ij]quinolin-
-4-one
##STR00178##
[0442] To
1,2,5,6-tetrahydro-8-(hydroxy(phenyl)(pyridin-4-yl)methyl)pyrrol-
o[3,2,1-ij]quinolin-4-one (70 mg, 0.20 mmol) in dry dichloromethane
(5 mL) was added by syringe trifluoroacetic acid (0.15 mL, 1.96
mmol), triethylsilane (95 .mu.L, 0.59 mmol) and
trifluoromethanesulfuric acid (0.05 equivalent) under an atmosphere
of nitrogen at 0.degree. C. The resulting solution was stirred at
ambient temperature for 48 h before it was washed with aqueous
NaHCO.sub.3 and water, dried over MgSO.sub.4 and concentrated in
vacuo. The residue was purified by flash chromatography on silica
gel (methanol/dichloromethane, 1/40, R.sub.f=0.1) to yield a pale
yellow solid (48 mg, 0.25 mmol, 72%). mp (methanol/dichloromethane)
168.degree. C. .sup.1H-NMR (500 MHz, CDCl.sub.3): .delta.=2.66 (t,
.sup.3J=7.7 Hz, 2H), 2.90 (t, .sup.3J=7.7 Hz, 2H), 3.13 (t,
.sup.3J=8.4 Hz, 2H), 4.07 (t, .sup.3J=8.4 Hz, 2H), 5.43 (s, 1H),
6.73 (s, 1H), 6.79 (s, 1H), 7.04 (d, .sup.3J=5.3 Hz, 2H), 7.08 (d,
.sup.3J=7.2 Hz, 2H), 7.26 (m, 1H), 7.32 (t, .sup.3J=7.4 Hz, 2H),
8.52 (d, .sup.3J=5.3 Hz, 2H). .sup.13C-NMR (125 MHz, CDCl.sub.3):
.delta.=24.4, 27.7, 31.5, 45.3, 56.1, 120.1, 124.3, 124.5, 126.5,
126.9, 128.6, 129.2, 129.2, 137.6, 140.3, 142.2, 149.9, 152.9,
167.5.
Example 79
Example of Activity
[0443] The biological in vitro assay systems (A-C) described below
were used for assessment of the inhibition of aldosterone synthase
(CYP11B2) by compounds of the present invention.
[0444] The following abbreviations are used:
DMEM: Dulbecco's Modified Eagle Medium
[0445] DMSO: Dimethyl sulfoxide EDTA: Ethylenediaminetetraacetic
acid EMMG: Edinburgh Minimal Medium with glycerol EtOAc: Ethyl
acetate FCS: Fetal calf serum HPLC: High pressure liquid
chromatography HPTLC: High performance thin layer
chromatography
A) Screening Assay in Transgenic Fission Yeast
[0446] A fission yeast suspension (S. pombe PE1) with a cellular
density of 3.times.10.sup.7 cells/ml was prepared from a freshly
grown culture using fresh EMMG (pH 7.4) modified according to Ehmer
et al (Ehmer, P. B. et al, J Steroid Biochem Mol Biol 81, 173-179
(2002)). An amount of 492.5 .mu.l of this cellular suspension was
mixed with 5 .mu.l of inhibitor solution (50 .mu.M of the compound
to be tested dissolved in ethanol or DMSO) and incubated for 15 min
at 32.degree. C. Controls were mixed with 5 .mu.l of ethanol. The
enzyme reaction was started by the addition of 2.5 .mu.l of
11-deoxycorticosterone (20 .mu.M, containing 1.25 nCi of
[4-.sup.14C]11-deoxycorticosterone, dissolved in ethanol), then it
was shaken horizontally at 32.degree. C. for 6 h. The test was
stopped by extracting the sample with 500 .mu.l of EtOAc. After a
centrifugation step (10000.times.g, 2 min), the EtOAc was pipetted
into a fresh cup and evaporated to dryness. The residue was
redissolved in 10 .mu.l of chloroform and the conversion of the
substrate to corticosterone was analyzed by HPTLC (see below).
[0447] The spots for the substrate deoxycorticosterone and the
resulting products corticosterone (and, if detectable,
18-hydroxycorticosterone and aldosterone) were quantified using the
relevant analysis program AIDA. For the human aldosterone synthase
expressed in S. pombe, only the product corticosterone and the
substrate deoxycorticosterone were quantified.
18-Hydroxycorticosterone and aldosterone were not formed in
detectable concentrations following an incubation period of 6 hours
and therefore did not enter into the analysis. The conversion was
calculated according to equation 1.
% P = [ PSL B ] - PSL HG [ PSL DOC + PSL B ] - 2 .times. PSL HG
.times. 100 Equation 1 ##EQU00001##
% P=conversion (percentage of total steroid of the product)
PSL=photon-stimulated luminescence (luminescence index)
PSL.sub.B=PSL for corticosterone (B) PSL.sub.DOC=PSL for
deoxycorticosterone (DOC) PSL.sub.HG=PSL of the background
[0448] The percentage inhibition that was caused by an inhibitor in
the concentration employed in each case was calculated according to
equation 2.
% H = [ 1 - % P H % P K ] .times. 100 Equation 2 ##EQU00002##
wherein % H=percentage inhibition % P=percentage conversion of the
substrate to products % P.sub.H=percentage conversion in the
presence of an inhibitor % P.sub.K=percentage conversion of the
control B) Test for CYP11B2 inhibitors (V79 MZh Cells): Maintenance
of the cells: V79 MZh11B2 and V79 MZh11B1, which recombinantly
express human aldosterone synthase (CYP11B2) or steroid
11-.beta.-hydroxylase CYP11B1) and were prepared according to
Denner et al. (Denner, K. et al., Pharmacogenetics 5:89-96 (1995)),
were cultured in cell culture dishes of 60 or 90 mm diameter in a
CO.sub.2 incubator at 37.degree. C. and in a water-saturated
atmosphere containing 5% of CO.sub.2. Both cell lines were cultured
in DMEM.sup.+, which contained 10% of FCS and the antibiotics
penicillin and streptomycin (1%) for protection from bacterial
contamination. The cells were passaged every 2 to 3 days following
treatment with trypsin/EDTA, since the doubling density, according
to cell count, was 1 to 2 days. The cells were passaged up to 12 to
15 times in order to exclude possible cell changes. If needed,
freshly thawed cells were employed.
TABLE-US-00001 DMEM.sup.+ medium DMEM powder medium 13.4 g
NaHCO.sub.3 3.7 g L-Glutamine (200 mM) 20.0 ml Penicillin (100
units/ml)/streptomycin (0.1 mg/ml) 10.0 ml Sodium pyruvate (100 mM)
10.0 ml Fetal calf serum (FCS) 100 ml H.sub.2O, double-distilled to
1 l
[0449] The pH of the medium was adjusted to 7.2 to 7.3. FCS was
added only after sterile filtration.
[0450] Inhibition test: V79 MZh11B2- and V79 MZh11B1 cells
(810.sup.5 cells per well) were grown to confluence in 24-well cell
culture plates with a 1.9 cm.sup.2 culture area per hole (Nunc,
Roskilde, Denmark). Before the test, the DMEM culture medium
present was removed, and 450 .mu.l of fresh DMEM with inhibitor
were added to each hole in at least three different concentrations
in order to determine the IC.sub.50 value. After preincubation (60
min, 37.degree. C.), the reaction was started by the addition of 50
.mu.l of DMEM containing 2.5 .mu.l of a solution of the substrate
11-deoxycorticosterone (20 .mu.M, containing 1.25 nCi of
[4-.sup.14C]11-deoxycorticosterone, in ethanol). The plate was then
kept in the CO.sub.2 incubator at 37.degree. C. and under 5%
CO.sub.2. The V79 MZh11B1 cells were incubated for 120 min, the V79
MZh11B2 cells for 40 min. Controls not containing inhibitor were
treated in the same manner. The enzyme reactions were stopped by
extraction of the supernatant with 500 .mu.l of EtOAc. The samples
were centrifuged (10000.times.g, 2 min), and the solution was
removed and evaporated. The residue was taken up in 10 .mu.l of
chloroform and analyzed by HPTLC (see below).
[0451] In the case of V79 MZh11B1, conversion was calculated
analogously to equation 1, wherein:
PSL.sub.B=PSL for cortisol and/or corticosterone PSL.sub.Doc=PSL
for deoxycortisol (RSS) and/or deoxycorticosterone
[0452] For V79 MZh11B2, the conversion followed according to
equation 3:
% P = [ PSL B + PSL 18 OHB + PSL Aldo ] - 3 .times. PSL HG [ PSL
DOC + PSL B + PSL 18 OHB + PSL Aldo ] - 4 .times. PSL HG .times.
100 Equation 3 ##EQU00003##
wherein % P=conversion (proportion of product in total steroid
PSL=photon-stimulated luminescence (luminescence index)
PSL.sub.B=PSL for corticosterone (B) PSL.sub.18OHB=PSL for
18-hydroxycorticosterone (18OHB) PSL.sub.Aldo=PSL for aldosterone
PSL.sub.DOC=PSL for 11-deoxycorticosterone (DOC) PSL.sub.HG=PSL of
the background
[0453] The percentage inhibition which was caused by an inhibitor
in the concentration employed in each case was calculated according
to equation 2.
[0454] Determination of the IC.sub.50 value: The IC.sub.50 value is
defined as the concentration of the inhibitor at which the enzyme
is inhibited to the extent of 50%. It was calculated by determining
the percentage inhibition at least 3 different inhibitor
concentrations, which must all lie in the linear range of the
sigmoidal IC.sub.50 curve (log C/% inhibition). The calculation was
carried out by linear regression. The values determined were only
used if they formed a straight line at a probability r of
>0.95.
HPTLC Analysis and Phospho-Imaging of the Radiolabeled
Steroids:
[0455] The resuspended residue from example A) or B)-containing the
radiolabeled steroids--was applied to an HPTLC plate (20.times.10
cm, silica gel 60F.sub.254) with a concentration zone (Merck,
Darmstadt, Germany). The plate was developed twice using the mobile
phase chloroform/methanol/water (300:20:1). Unlabeled
11-deoxycorticosterone and corticosterone were applied as a
reference for the CYP11B1 reaction. For the CYP11B2 reaction,
11-deoxycorticosterone, corticosterone, 18-hydroxycorticosterone
and aldosterone were used as a reference. The unlabeled references
were detected at 260 nm. Subsequently, imaging plates (BAS MS2340,
for .sup.14C samples, Raytest, Straubenhardt, Germany) were exposed
for 48 h with the HPTLC plates. The imaging plates were scanned
using the Phosphoimager system Fuji FLA 3000 (Raytest,
Straubenhardt, Germany) and the steroids were quantified.
[0456] Using the in vitro test systems (A, B) described above;
exemplary compounds of the present invention show inhibitory
effects of human aldosterone synthase (CYP11B2) in the range of
from >80% to >98% inhibition [inhibitor concentration=2.5
.mu.M, test system A (transgenic fission yeast S. pombe PE1);
inhibitor concentration=0.5 .mu.M, test system B (V79
MZh11B2)].
[0457] The determined IC.sub.50 values of the compounds of the
present invention using the in vitro test system B (V79 MZh11B2)
described above lie in a concentration range of from 10.sup.-3
mol/l to 10.sup.-10 mol/l. The biological test data for exemplary
compounds are summarized in Table 1 and Table 2.
TABLE-US-00002 TABLE 1 % IC.sub.50 (.times.10.sup.-9 mol/l).sup.b
(0.5 .mu.M).sup.a V79 11B2 V79 11B1 Example hCYP11B2 hCYP11B2
hCYP11B1 1 88 28 6746 2 92 2.6 742 6 94 0.2 87 9 93 21 5972 12 97
3.8 1671 .sup.ainhibitor concentration employed (test system B)
.sup.btest system B, the selectivity of the test substances toward
CYP11B1 results from the ratio IC.sub.50(11B1)/IC.sub.50(11B2)
TABLE-US-00003 TABLE 2 % % (0.5 .mu.M).sup.a (0.5 .mu.M).sup.a
Example hCYP11B2 hCYP11B1 7 99 97 8 97 49 14 92 49 19 95 51 28 87
24 .sup.ainhibitor concentration employed (test system B)
C) Test for Selective CYP11B2 Inhibitors (NCI-H295R Cells):
[0458] The NCI-H295R cell line is commercially available and is
often used as a model for the human adrenal cortex. The cell line
was isolated for the first time in 1980 from an invasive
adrenocortical tumor of a patient (Gazdar, A. F. et al., Cancer
Res. 50:5488-5496 (1990)). The cells contain 5 steroidogenic CYP450
enzymes, among them CYP11B2 and CYP11B1. Since all steroidogenic
CYP enzymes that occur in the adrenal cortex are expressed in this
cell line, it is an important tool in the estimation of the
selectivity of inhibitors in vitro.
[0459] The NCI-H295R cells were ordered through LGC-Promchem
(Wesel). The DMEM:Ham's F12-medium, glutamine and
penicillin/streptomycin were obtained from c.c.pro, Neustadt/W.
ITS.sup.+Premix originated from BD Biosciences, Heidelberg and
Ultroser SF from the company Pall BioSepra SA, (Cergy Saint
Christophe, France).
[0460] The NCI-H295R cells were cultured in DMEM:Ham's F12 medium
(1:1), 1.25% glutamine, 1% penicillin/streptomycin, 1%
ITS.sup.+Premix, 2% Ultroser SF in 90 mm dishes (NUNC
International, Wiesbaden) in a CO.sub.2 incubator at 37.degree. C.
under 5% CO.sub.2. Change of medium was carried out every 48 hours.
The cell lines were cultured and passaged until a confluent cell
layer was formed. The cell, material was obtained by trypsin
treatment and the cell count was determined with the aid of a
CASY.RTM.TT cell counter (150 .mu.l capillary). By diluting the
suspension with DMEM:Ham's F12, the cell density was adjusted to
1.times.10.sup.6 cells/ml. 1 ml of the cell suspensions thus
obtained was placed in each hole of a 24-well plate. It was
possible to coat two 24-well plates using the cell material of two
confluently grown culture dishes. After 24 hours, the cells had
grown and could be employed after a further 24-hour stimulation
phase for the test with potassium ion-containing solution (final
concentration: 20 mM KCl).
Execution of the CYP11B2 Test (NCI-H295R):
[0461] Preincubation: The medium was aspirated and replaced by 450
.mu.l of DMEM:Ham's F12, to which the inhibitor was added in the
appropriate concentration (final concentration of the inhibitor in
the final volume (500 .mu.l) of the test: 2.5 .mu.M). It was then
preincubated for 1 h. The control batches contained 1% ethanol.
[0462] Start of test: the reaction was initiated by the addition of
the substrate, dissolved in 50 .mu.l of DMEM:Ham's F12
(deoxycorticosterone (DOC) or corticosterone (B), final
concentration of the substrate: 0.5 .mu.M). The substrate solutions
were in each case a mixture of unlabeled and [.sup.3H]-labeled
substrates. The 24-well plate was then kept at 37.degree. C. under
5% CO.sub.2 in a CO.sub.2 incubator. When using DOC as a substrate,
the incubation period was 3 h, when using B it was 24 h.
[0463] Termination of test: After expiration of the incubation
periods, the contents of the well were removed and inactivated by
mixing with 1000 .mu.l of dichloromethane in a 2 ml Eppendorf cup.
They were shaken for 10 minutes and then centrifuged for phase
separation, and the organic phase was transferred to a 1.5 ml
Eppendorf cup. The solvent was evaporated overnight, and the
residue was resuspended in 20 .mu.l of acetonitrile/water (50:50).
Separation of the steroids was carried out using an Agilent 1000
HPLC equipped with a radioactivity and UV detector. The stationary
phase used was a C18 reverse-phase column (Nucleodur C18ec, 100-3,
2.times.125 mm, Macherey-Nagel). The steroids were eluted by means
of a water/acetonitrile mixture (flow rate 0.7-0.8 ml/min). To
enhance the radioactivity signals, a scintillation fluid
(Quickszint Flow 302, Zinsser) was admixed in the ratio 1:2. By
integration of the peak areas under the resulting chromatograms
(determination using the HPLC evaluation software
ChemStation.RTM.), it was possible to determine the conversion of
the enzyme reaction.
[0464] The percentage inhibition caused by an inhibitor in the
respective concentration employed is calculated according to
equation 2:
% H = [ 1 - % P H % P K ] .times. 100 Equation 2 ##EQU00004##
% H=percentage inhibition % P=percentage conversion of the
substrate to products % P.sub.H=percentage conversion with
inhibitor % P.sub.K=percentage conversion of the control
[0465] The IC.sub.50 value was calculated by determining the
percentage inhibition at least 3 different inhibitor
concentrations, which must all lie in the linear range of the
sigmoidal IC.sub.50-curve (% inhibition/log C). Calculation was
carried out by linear regression. The values determined were only
used if the regression of the straight line was >0.95.
[0466] The CYP11B1 test was carried out in analogy to the CYP11B2
test as described above. The substrate solution was a mixture of
unlabeled and [.sup.3H]-labeled deoxycortisol (RSS). The incubation
period was 12 h.
[0467] The disclosure of all documents referred to in the present
application, such as, for example, journal articles, books,
patents, and patent applications, is hereby included in the
specification by way of reference.
* * * * *